Overview of Immunosupressionsin

Adult Liver transplantation

DrBhavin Vasavada

MBBSMSFellow HPB and liver transplant surgery

First extended survival of Liver Transplant (1 year)

Precyclosporin Era

bull Corticosteroids and azathioprine were used in combination by Starzl et al in his first 5 transplants

bull The majority of the Colorado series from 1963 to 1976 received corticosteroids azathioprine and antilymphocyte globulin

Gastroenterology 1979 August 77(2) 375ndash388 Fifteen Years of Clinical Liver Transplantation THOMAS E STARZL

bull Survival in the Early and Late Phases of the Colorado Experience (Follow-up to January 1979)

bull Primary cause of death was ACR in 20 of cases

Time period No of patients One year survival

1963-1976 111 28

1976-1977 30 50

First extended survival of Liver Transplant (1 year)

Precyclosporin Era

bull Corticosteroids and azathioprine were used in combination by Starzl et al in his first 5 transplants

bull The majority of the Colorado series from 1963 to 1976 received corticosteroids azathioprine and antilymphocyte globulin

Gastroenterology 1979 August 77(2) 375ndash388 Fifteen Years of Clinical Liver Transplantation THOMAS E STARZL

bull Survival in the Early and Late Phases of the Colorado Experience (Follow-up to January 1979)

bull Primary cause of death was ACR in 20 of cases

Time period No of patients One year survival

1963-1976 111 28

1976-1977 30 50

Precyclosporin Era

bull Corticosteroids and azathioprine were used in combination by Starzl et al in his first 5 transplants

bull The majority of the Colorado series from 1963 to 1976 received corticosteroids azathioprine and antilymphocyte globulin

Gastroenterology 1979 August 77(2) 375ndash388 Fifteen Years of Clinical Liver Transplantation THOMAS E STARZL

bull Survival in the Early and Late Phases of the Colorado Experience (Follow-up to January 1979)

bull Primary cause of death was ACR in 20 of cases

Time period No of patients One year survival

1963-1976 111 28

1976-1977 30 50

Gastroenterology 1979 August 77(2) 375ndash388 Fifteen Years of Clinical Liver Transplantation THOMAS E STARZL

bull Survival in the Early and Late Phases of the Colorado Experience (Follow-up to January 1979)

bull Primary cause of death was ACR in 20 of cases

Time period No of patients One year survival

1963-1976 111 28

1976-1977 30 50

Cyclosporinbull First successful use of cyclosporin in 2

patients of liver transplant without rejection

bull 14 patients who underwent liver transplant were given cyclosporin as Immnosupressant

Transplant Proc 1988 Feb20(1 Suppl 1)498-504Experience in 1000 liver transplants under cyclosporine-steroid therapy a survival

reportIwatsuki S Starzl TE Todo S Gordon RD Esquivel CO Tzakis AG Makowka L Marsh JW

Koneru B Stieber A et al

bull 14 patients who underwent liver transplant were given cyclosporin as Immnosupressant

Transplant Proc 1988 Feb20(1 Suppl 1)498-504Experience in 1000 liver transplants under cyclosporine-steroid therapy a survival

reportIwatsuki S Starzl TE Todo S Gordon RD Esquivel CO Tzakis AG Makowka L Marsh JW

Koneru B Stieber A et al

Transplant Proc 1988 Feb20(1 Suppl 1)498-504Experience in 1000 liver transplants under cyclosporine-steroid therapy a survival

reportIwatsuki S Starzl TE Todo S Gordon RD Esquivel CO Tzakis AG Makowka L Marsh JW

Koneru B Stieber A et al

bull can be administered intravenously although it is usually given orally as a tablet or an oral suspension

bull After oral administration cyclosporine is variably absorbed in the jejunum and enters the lymphatic system

bull Peak blood levels are achieved in two to four hours

bull Cyclosporine levels should be monitored frequently in the peritransplant period (typically daily) with decreasing frequency as graft function stabilizes and rejection becomes less of a threat

Cyclosporine

bull Block Calcineurinrarr darrIL-2 rarrdarrT-Cell Activation

bull Initial dosage 10 to 15 mgkgday divided into 2 doses

bull Trough Goalsndash Week 1-2 250-350 ngmL

ndash Weeks 3-4 200-300

ndash Weeks 5-24 150-250 ngmL

ndash Weeks 25+ 100-200 ngmL

ndash Distant ndash can tolerate levels lt100

Cyclosporine ndash Adverse Effects

bull Hypertension

bull Renal dysfunction

bull Hirsutism

bull Hyperkalemia

bull Gingival hyperplasia

bull Hypomagnesemia

bull Neurologic toxicity

httpjorthodmaneyjournalsorgcontentvol30issue1imageslargeClocFig1bjpeg

TACROLIMUS

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Cyclosporine levels should be monitored frequently in the peritransplant period (typically daily) with decreasing frequency as graft function stabilizes and rejection becomes less of a threat

Cyclosporine

bull Block Calcineurinrarr darrIL-2 rarrdarrT-Cell Activation

bull Initial dosage 10 to 15 mgkgday divided into 2 doses

bull Trough Goalsndash Week 1-2 250-350 ngmL

ndash Weeks 3-4 200-300

ndash Weeks 5-24 150-250 ngmL

ndash Weeks 25+ 100-200 ngmL

ndash Distant ndash can tolerate levels lt100

Cyclosporine ndash Adverse Effects

bull Hypertension

bull Renal dysfunction

bull Hirsutism

bull Hyperkalemia

bull Gingival hyperplasia

bull Hypomagnesemia

bull Neurologic toxicity

httpjorthodmaneyjournalsorgcontentvol30issue1imageslargeClocFig1bjpeg

TACROLIMUS

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Cyclosporine

bull Block Calcineurinrarr darrIL-2 rarrdarrT-Cell Activation

bull Initial dosage 10 to 15 mgkgday divided into 2 doses

bull Trough Goalsndash Week 1-2 250-350 ngmL

ndash Weeks 3-4 200-300

ndash Weeks 5-24 150-250 ngmL

ndash Weeks 25+ 100-200 ngmL

ndash Distant ndash can tolerate levels lt100

Cyclosporine ndash Adverse Effects

bull Hypertension

bull Renal dysfunction

bull Hirsutism

bull Hyperkalemia

bull Gingival hyperplasia

bull Hypomagnesemia

bull Neurologic toxicity

httpjorthodmaneyjournalsorgcontentvol30issue1imageslargeClocFig1bjpeg

TACROLIMUS

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Cyclosporine ndash Adverse Effects

bull Hypertension

bull Renal dysfunction

bull Hirsutism

bull Hyperkalemia

bull Gingival hyperplasia

bull Hypomagnesemia

bull Neurologic toxicity

httpjorthodmaneyjournalsorgcontentvol30issue1imageslargeClocFig1bjpeg

TACROLIMUS

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

TACROLIMUS

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Randomized Control Trial

bull Total number of patient 478 adults 51 children

bull Randomly assigned either tacrolimus (n=263) and cyclosporin (n=266)

bull Follow up period of one year

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Figure 1 patient survival

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Figure 2 Graft survival

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

A Acute rejection BSteroid resistant acute rejection

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Tacrolimus

bull MOA same as CsA

bull Initial dose 01 to 015 mgkgday orally

bull Trough Goals (variable per patientdisease)

ndash Early Post-OLT ndash 10-15 ngml

ndash 3-6 Months ndash 8-10

ndash gt6 Months ndash 5-7 (variable)

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Tacrolimus dosing should be individualized

bull start with a low dose (05 to 1 mg every

bull 12 hours) on postoperative day one and aim for a level of 7 to 10 ngmL by the end of the first week

bull Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Tacrolimus ndash Adverse Effects

bull Posttransplant diabetes mellitus

bull Nausea vomiting diarrhea

bull Hyperkalemia

bull Tremor

bull Hypertension

bull Hypomagnesemia

bull Headache

bull Renal dysfunction

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Tac vs Csa

bull Dyslipidemia and Gingival hyperplasia ndash more common in Csa

bull Diabetes ndash more common in Tac

bull Rejection ndash less common in Tac

bull Renal Dysfunction ndash similar

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Baseline change in creatinine clearence at 52 weeks

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Calcineurin inhibitors and HCV

bull The selection of a specific calcineurin inhibitor in liver transplant recipients with HCV remains unclear

bull A theoretical advantage of cyclosporine is that it inhibits HCV replication in vitro

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Sirolimus

bull Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionbull blocks response of T and B Cell Activation by cytokines ndash prevents

progression at the juncture of G1 and S phase in these cell lines

bull Theoretical (lab based) antineoplastic and antifungal effects

bull Early excitement about renal protective effect-subsequent studies have not confirmed thisndash Meta-analysis of 11 studies suggests a numericalnon-

significant improvement in renal function

Hepatology 2010 Oct52(4)1360-70

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Sirolimus

bull Not FDA approved for Liver Transplants ndash

ndash The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune) The trial was conducted by sirolimus manufacturer Wyeth

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Although sirolimus binds its target (FK-binding protein) with higher affinity than tacrolimus the two drugs act synergistically rather than competitively to prevent rejection

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Sirolimus

bull Black Box warning ndash possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting ndash usually wait up to 12 weeks post

bull Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06112009])

bull Currently using in those intolerant to CNIs and in some patients for theoretical antineoplastic and renoprotective (controversial) effects

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Sirolimus ndash Adverse Effects

bull Anemiabull Hypercholesterolemiabull Hypertriglyceridemiabull Leukopeniabull Hyperlipidemiabull Interstitial lung diseasebull Thrombocytopeniabull Peripheral edemabull Wound dehiscencebull Hepatic Artery Thrombosis

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Mycophenylate Mofetil (MMF)Mycophenolic Acid (MPA)

bull inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides

bull Leads to blockage of DNA replication in T and B lymphocytes (canrsquot use salvage pathways)

bull MPA is a delayed release form of MMF bull Dosing ndash

ndash 1000-1500mg bid MMF or ndash 360-720 BID MPA

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Side effects of MMFMPA

bull Nausea vomiting diarrhea

bull Anemia

bull Leukopenia

bull Weight loss

bull Thrombocytopenia

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull The role of MMF is similar to that of sirolimusin that it is used to reduce or discontinue CNI dosing in order to treat side effects

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Steroid

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Once the patient is able to take oral medications heshe is switched to prednisone 20 mgday

bull Tapering to zero is usually achieved over three to six months although some centers leave patients on 5 mgday

bull indefinitely

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull Given the problems with glucocorticoids many centers try to wean from steroids as early as possible

bull rapid steroid withdrawal can precipitate a flare of an underlying condition (eg autoimmune hepatitisinflammatory bowel disease or hepatitis)

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Glucocorticoids and HCV

bull The ability of steroids to increase HCV replication has created concern about their use in these patients

bull As a general rule three options exist with regard to glucocorticoid use in patients with HCV

bull Maintain low dose steroids indefinitely (approximately 5 mgday)

bull Taper steroids slowly

bull Avoid steroids

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Steroid free immunosupression

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Limitation of steroid free regime

bull Trials cannot necessarily be compared since steroid dosing and tapering regimens vary widely

bull We rarely see rejection using the steroid protocol discussed above

bull shorter tapering protocols have been associated with higher rates of rejection including steroid-resistant rejection

bull The steroid-free regimens use expensive drugs that are not always available Daclizumab is no longer manufactured

bull Aggressive immunosuppression may have late consequences such as post-transplant lymphoproliferative disease (PTLD)

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Baciliximab (Simulact)

IL-2 Receptor Antibodies ndash inductionBasiliximab (Simulect) daclizumab (Zenapax)

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Immunosuppression ndash Drug Interactions

bull Cytochrome P-450 3A

bull P-Glycoprotein ndash cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney) ndash carvedilol inhibits p-plycoprotein pathway leading

to increased CNI levels

bull Grapefruit ndash can increase levels of CNIs ndashmechanism not totally clear

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Drug Interactions

American Journal of Transplantation 2009 9 1988ndash2003

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Antibody Induction

bull Antithymocyte Globulin ndash inductionrejectionndash Polyclonal antilymphocyte globulin ndash multiple epitopes on

T cell receptor ndash lead to apoptosis of T-cellsndash ATGAM (of equine origin) ndash Thymoglobulin (of rabbit origin)

bull Monoclonal anti T-Cell antibodies ndash inductionrejectionndash Muromonab-CD3 (OKT3) ndash binds CD3 Antigen on T-Cell

receptor ndash inactivates adjacent T-Cell ndash leads to rapid drop in T-Cells

bull IL-2 Receptor Antibodies ndash inductionndash Basiliximab (Simulect) ndash daclizumab (Zenapax)

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

Summary

bull CsA Tac or Sirolimus are the backbone of maintenance immunosuppresion

bull Addition of other agents (Steroids MMF Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents

bull 50 of post-OLT deaths are directlyindirectly related to immunosuppressive medications

bull THANK YOU

bull THANK YOU