Transplant Immunosuppression

Transplant Immunosuppression

Steven Gabardi, PharmD, BCPS, FAST, FCCP Abdominal Organ Transplant Specialist

Department of Transplant Surgery

Brigham and Women’s Hospital

Assistant Professor of Medicine

Harvard Medical School

Steven Gabardi, PharmD, BCPS, FAST, FCCP

• Butler University College of Pharmacy

• Pharmacy Residency at Tufts Medical Center

• Abdominal Organ Transplant Clinical Pharmacist at Brigham and Women’s Hospital

• Assistant Professor of Medicine Harvard Medical School

• Clinical focus: Renal Transplant

• Research focus: Infection in Transplant; Long-term Management of Transplant Recipients

Conflict of Interest

• I have no pertinent financial relationships to disclose.

• My presentation does include discussion of off-label or investigational use

Objectives

• Outline the principles of immunosuppression in kidney transplant recipients

• Classify and describe the mechanism of action of different immunosuppressive agents used in kidney transplantation

• Identify the different uses of transplantation immunosuppression and the relative benefits and drawbacks of different immunosuppressive agents

• Discuss the treatment of acute rejection and antibody-mediated rejection

Timeline of Drug Development

80

6560 60

45 45

3535

25

151410 9

40

6065 65

8590 9090 90

9596 96

'60 '65 '70 '75 '80 '85 '90 '95 '00 '04 '09 '14

Pe

rce

nta

ge

Year

Rejection @ 1 year 1 Year Survival

•Radiation

•Prednisone

•6-MP

•AZA

•ATGAM

•Cyclosporine

•OKT3

•Modified Cyclosporine

•Tacrolimus

•Myocophenolate mofetil

•Daclizumab

•Basiliximab

•Rabbit antithymocyte

globulin

•Sirolimus•Belatacept

Immunosuppressant Action and the Immune Cascade

Gabardi S, Kim M. Immunosuppression – Renal Transplantation. Nephrology, Dialysis and Transplantation 2019.

Poll Question:

• Age/Sex/Race: 33 y/o male • Cause of renal failure: IgA nephropathy - focal

proliferative type- current Cre 5.88/eGFR 11 more symptomatic with recent wt loss 15 lbs and fatigue

• Dialysis status: Pre-emptive • Potential donors: Mom cleared for donation• Prior Transplant: no• PMH: non contributory• Immunological risk:

– Prior transfusion/pregnancy/transplant: no– Previous immunosuppression: no– Prior cancer: no– Prior severe infections: no

• EBV pos; CMV neg; HCV neg ;HBV neg ;HIV neg• PRA class I: Neg; PRA class II: Neg• Planned Maintenance Immunosuppression: TAC,

MPA, early steroid withdrawal

• What would you give for Induction Therapy:

1. Alemtuzumab

2. Basiliximab

3. Rabbit antithymocyte Globulin

4. No induction therapy

Induction

Goals of induction therapy

1. To decrease the rate of acute rejection

2. To permit delayed initiation, minimization or avoidance of some of the maintenance agents (i.e. CNI, corticosteroids)

Available agents

1. Monoclonal antibodies that react with a single antigen receptor on the lymphocyte• Basiliximab (Simulect®)

• Alemtuzumab (Campath®)

• Withdrawn from the market: muromonab-CD3 (OKT3) and daclizumab (Zenapax®)

2. Polyclonal antibodies: react with multiple antigen receptors• Equine polyclonal IgG antibody (ATGAM®)

• Rabbit polyclonal IgG antibody (Thymoglobulin®)

Non-Depleting Proteins: Basiliximab• A chimeric monoclonal antibody that competitively

inhibits the activation of lymphocytes by IL-2

• This agent has low immunogenicity potential because of the incorporation of human protein sequences.

Human

Mouse

BasiliximabPoints of Discussion Basiliximab Characteristics

Formulation ‐ Reconstituted (preservative free) 10 and 20 mg vials

Dosing ‐ 20 mg given 2 hours prior to transplant, then 20 mg on post-op day 4

Administration ‐ IV infusion over 20-30 minutes via central or peripheral line‐ Consider premedication prior to infusions‐ Some centers may not administer diphenhydramine and/or acetaminophen and choose to

administer basiliximab within 1 hour of the patient’s scheduled steroid dose

Monitoring ‐ No Therapeutic Drug Monitoring (TDM)‐ Clinical Monitoring:

‐ Hypersensitivity reactions: severe, acute (onset within 24 hours) have been observed‐ Hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema,

respiratory failure, urticaria, rash, or pruritus.

PharmacokineticConsiderations

‐ Distribution = 8.6 + 4.1 L‐ Total body clearance = 41 ± 19 mL/hr ‐ Terminal elimination half-life (t½) = 7.2 + 3.2 days

Basiliximab

Points of Discussion Basiliximab Characteristics

Duration of Activity ‐ Basiliximab concentrations of 0.2 mg/L or more provide significant IL-2 receptor saturation.

‐ Total basiliximab doses from 20 to 60 mg yield receptor-saturating concentrations for up to 8 weeks post-transplant.

‐ A cumulative dose of 40 mg offers the best balance between receptor suppression (up to 45 days) while avoiding pronounced potential for prolonged suppression.

Onrust SV, et al. Drugs 1999;57:207-13; Mentre F, et al. J Pharmacokinet Biopharm 1999;27:213-30; Kovarik J, et al. Transplantation 1997;64:1701-5.

Depleting Proteins: AntithymocyteGlobulins (Horse and Rabbit)• The antithymocyte globulins (ATG) are purified gamma globulin

obtained by immunizing an animal w/ human thymocytes. • Cytotoxic antibodies directed against a broad array of surface antigens

expressed on T- and B-cells

CD1a

CD3/TCR

CD4

CD6

CD7

CD8

CD16

CD19

CD20*

CD25*

CD6

CD11a/CD18 (LFA-1)

CD44

CD49/CD29 (VLA-4)

CD50 (ICAM-3)

CD51/61

CD54 (ICAM-1)

CD56*

CD58 (LFA-3)

LPAM-1(α4β7)

CD102 (ICAM-2)

CD195 (CCR5)

CD197 (CCR7)

CD184 (CXCR4)

CD2

CD5

CD11b

CD29

CD38

CD40

CD45

CD52

CD95

CD126

CD138

CD28*

CD30

CD32

CD40

CD80*

CD86

CD152 (CTLA-4)

HLA class I

HLA DR

β2-M

Immune Response

Antigens

Adhesion &

Cell TraffickingHeterogeneous

Pathways

Ankersmit HJ, et al. Am J Transplant. 2003;3:743. Bourdage JS, et al. Transplantation. 1995;59:1194. Michallet M-C, et al. Transplantation.2003;75:657. Monti P, et al. Int Immunopharmacol. 2003;3:189. Pistillo MP, et al. Transplantation. 2002;73:1295. Préville X, et al. Transplantation. 2001;71:460. Rebellato LM, et al. Transplantation. 1994;57:685. Tsuge I, et al. Curr Ther Res. 1995;56:671. Zand M, et al. Transplantation. 2005;79:1507. Zand MS, et al. Blood. 2006;107:2895.

Depleting Proteins: Antithymocyte Globulins (Horse and Rabbit)

Macrophage

ATG

T Cell

Opsonization

Phagocytosis

Complement

cascade

Lysis

Membrane attack

complex

ATG ATG

Apoptosis

T Cell

T Cell

Macrophage

Genestier L, et al. Blood. 1998;91:2360. Préville X, et al. Transplantation. 2001;71:460.

Antithymocyte Globulins (Horse and Rabbit)

Lopez M, et al. J Am Soc Nephrol 2006: 17: 2844-53.

CD4+

T cell

Apoptosis

Anergy

Memory

Effector

Termination

Regulation

Donor

APC

Signal 1

Signal 2

Activation

Indirect

Pathway

Direct

Pathway

B cell help

DTH

CTL help

CD4+CD25+Foxp3+

Self APC

• Immunomodulation

• Immune reconstitution generally occurs within 2-4 months following ATG induction, but in some patients it may persist for years.

• rATG-mediated immunosuppression also appears to be attributable in part to immunologically specific actions involving the generation of CD4+CD25+Foxp3+ regulatory T-cells.

• In vitro, rATG has the unique ability to convert CD4+CD25- T-cells into CD4+CD25+ T-cells within 24 hrs.


Points of Discussion Rabbit ATG Characteristics Horse ATG Characteristics

Formulation ‐ Reconstituted 25 mg vial ‐ Ampule 250 mg per 5 mL

Dosing ‐ Cumulative doses of 3-6 mg/kg, generally given in doses of 0.75-1.5 mg/kg/day x 1-8 doses

‐ 5-15 mg/kg/day for 4-14 days

Administration ‐ IV via central or peripheral line‐ Peripheral administration: consider addition

of heparin and hydrocortisone in a larger volume

‐ The manufacturer recommends that the first dose be administered over 6 hours and that subsequent doses be given over 4 hours.

‐ Infusion rates may be reduced in those that experience any infusion-related reactions

‐ Premedicate with steroids, diphenhydramine and acetaminophen

‐ IV via central ‐ Administer over at least 4 hours

‐ Peripheral line is not recommended‐ Premedicate with steroids, diphenhydramine

and acetaminophen ‐ An intradermal skin test (5 mcg or 0.1 mL)

should be performed prior to administering infusion.

‐ Observe patient q15-20 mins over the 1st hour after skin test.

‐ Local reaction of >10 mm with a wheal or erythema, with or without pseudopod formation and itching, or marked local swelling = positive test.



Contraindication ‐ Allergy to rabbit proteins or serum ‐ Allergy to horse proteins or serum

Monitoring ‐ No TDM, but some centers monitor T-cell depletion

‐ WBC (lymphocytes <200/mm3)or CD3+ T-cells (<20/mm3) performed daily or three times a week.

‐ Clinical Monitoring: ‐ Infusion-related reactions (i.e., pain,

swelling, erythema)‐ Immune-mediated reactions (i.e., fever,

chills, hypotension, tachycardia, edema, myalgia)

‐ Myelosuppression‐ WBC 2,000-3,000 cells/mm3 = ½ dose; <

2,000 = hold/discontinue‐ Platelets 50,000-75,000 cells/mm3 = ½ dose;

<50,000 = hold/discontinue

‐ No TDM‐ Clinical Monitoring:

‐ Stop infusion immediately if a systemic reaction (i.e., dyspnea, tachycardia, hypotension, or skin reaction) or anaphylaxis occurs.

‐ Other infusion- related or immune-mediated reactions (i.e., fever, chills, chest pain, myalgia, etc.)

‐ Myelosuppression



Pharmacokinetic Considerations

‐ The terminal t½ was found to be highly variable as elimination is dependent on the individual patients’ elimination of the foreign protein

‐ Mean plasma t½ = 2-3 days

‐ Terminal elimination t½ = 5.7 + 3 days

Duration of Activity ‐ It takes approximately 3 months for a patient’s immune system to be fully reconstituted.

‐ It takes approximately 3 months for a patient’s immune system to be fully reconstituted.

Depleting Proteins: Alemtuzumab

• Alemtuzumab is an anti-CD52 humanized, monoclonal antibody that has an FDA indication for use in B-cell chronic lymphocytic leukemia and multiple sclerosis.

• CD52 is present on virtually all B- and T-cells, as well as macrophages, NK cells and some granulocytes.

• The alemtuzumab-CD52 complex triggers antibody-dependent lysis.

Complement

cascade

Lysis

Membrane attack

complex

Alemtuzumab

T Cell

CD52

Alemtuzumab

Points of Discussion Alemtuzumab Characteristics

Formulation ‐ Vial (preservative free) 30 mg/mL ; 1 mL vial

Dosing ‐ 30 mg given as a single dose intraoperatively

Administration ‐ IV infusion over 2 hours via a dedicated line‐ Premedicate with diphenhydramine and acetaminophen 30 minutes prior to infusion. If patient

is receiving corticosteroids, it is appropriate to administer prior to an alemtuzumab infusion.

‐ SC administration less commonly causes chills or infusion-related reactions, but may cause injection site reactions that warrant premedication

Monitoring ‐ No TDM, but some centers will monitor the long-term effects of alemtuzumab by monitoring CD4+ counts

‐ Clinical Monitoring: ‐ Infusion-related reactions (i.e., nausea, vomiting, diarrhea, headache, dysthesias and dizziness)‐ Immune-mediated reactions (i.e., fever, chills, hypotension, tachycardia, edema, myalgia)‐ Myelosuppression

Alemtuzumab

Points of Discussion Alemtuzumab Characteristics

PharmacokineticConsiderations

‐ Based on multi-dose CLL studies‐ Volume of Distribution (Vd) = 0.18 L/kg‐ Terminal elimination half-life t½ = 11 hours (single-dose data)

Duration of Activity ‐ The depletion of lymphocytes is so marked that it takes several months, in some cases more than one year, post-administration for a patient’s immune system to be fully reconstituted.

Special Considerations ‐ Clinical Considerations‐ One major concern with alemtuzumab is that B cell depletion and reconstitution may promote

formation of donor specific antibodies (DSA), potentially resulting in a chronic humoral response.

‐ Distribution‐ As of September 4, 2012, alemtuzumab is no longer commercially available, but is provided

through the Campath Distribution Program free of charge. ‐ In order to receive alemtuzumab, the healthcare provider is required to document and comply

with certain requirements.‐ Campath Distribution Program can be found at www.campath.com or reached at 1-877-422-

6728

Todeschini M, et al. J Immunol 2013;191:2818-28

http://www.campath.com/

Comparative Analyses of Induction Therapies

• e-ATG vs. r-ATG1-3

• Efficacy: Significantly lower rates of BPAR and improved allograft/patient survival with r-ATG at 1-, 5- and 10-years

• Safety: Significantly lower rates of CMV infection with r-ATG, despite higher early rates of leukopenia. Similar rates of PTLD.

• Basiliximab vs. r-ATG (high risk recipients)4

• Efficacy: Similar composite end point of BPAR, DGF, allograft/patient survival

• Significantly lower rates of BPAR associated with r-ATG

• Safety: Significantly higher rates of myelousppression and overall infections seen with r-ATG

• Significantly fewer cases of CMV infection seen with r-ATG, despite higher early rates of leukopenia.

• Alemtuzumab vs. Basilximab (low-risk); vs. r-ATG (high-risk) 5

• Efficacy vs. Basiliximab: Lower rates of BPAR at 6, 12 and 36 months with alemtuzumab. The composite endpoint of freedom from rejection, graft loss or death was significantly better at 3-years with alemtuzumab.

• SAFETY: lower rates of serious infectious complications seen with basiliximab.

• Efficacy vs. r-ATG: The composite endpoint of freedom from rejection, graft loss or death was similar between both agents.

• SAFETY: overall, more infectious disease seen with r-ATG, but similar rates of serious infectious complications.

1. Brennan DC, et al. Transplantation 1999;67:1011-8. 2. Hardinger KL, et al. Transplantation 2004;78:136-41. 3. HardingerKL, et al. Transplantation 2008;86:947-52. 4. Brennan DC, et al. N Engl J Med 2006;355:1967-77. 5. Hanaway MJ, et al. N Engl J Med 2011;364:1909-19.

United States OPTN Data for use of Induction Therapies Among Kidney Transplant Recipients

• Induction therapy is commonplace among renal transplant recipients:

• Induction therapy was used in 91.9% of renal transplants

• The majority of patients treated in the US receive a T‐cell depleting agent.

• Acute rejection at 1 year:• IL-2 RA = 8.4%

• Antilymphocyte antibody = 6.9%

• No induction = 6.6%

Clinical Data – Kidney Transplant

• eATG vs. rATG1-3

• Efficacy: Significantly lower rates of BPAR and improved allograft/patient survival with rATG at 1-, 5- and 10-years

• Safety: Significantly lower rates of CMV infection with rATG, despite higher early rates of leukopenia. Similar rates of PTLD.

1. Brennan DC, et al. Transplantation 1999;67:1011-8. 2. Hardinger KL, et al. Transplantation 2004;78:136-41. 3. Hardinger KL, et al. Transplantation 2008;86:947-52.


• Basiliximab vs. rATG (high risk recipients)

• Efficacy: Similar composite end point of BPAR, DGF, allograft/patient survival

• Significantly lower rates of BPAR associated with rATG

• Safety: Significantly higher rates of myelosuppression and overall infections seen with rATG

• Significantly fewer cases of CMV infection seen with rATG, despite higher early rates of leukopenia.

Brennan DC, et al. N Engl J Med 2006;355:1967-77


• Alemtuzumab vs. Basiliximab (low-risk); vs. rATG (high-risk)• Efficacy vs. Basiliximab: the incidence of BPAR was lower in the alemtuzumab group in comparison to the

basiliximab group at 6-, 12- and 36-months post-transplant (2% vs. 18%, 3% vs. 20%, and 10% vs. 22%, respectively).

• The composite endpoint of freedom from rejection, graft loss or death was significantly better at 3-years with alemtuzumab.

• Late rejection, which the authors defined as BPAR occurring between months 12 and 36 in patients who did not have BPAR within the first 12 months, occurred in numerically higher rates in patients induced with alemtuzumab (8% vs. 3%, respectively), but, did not reach statistic significance.

• SAFETY: lower rates of serious infectious complications seen with basiliximab.

• Efficacy vs. rATG: BPAR was similar between alemtuzumab and rATG at 6-, 12- and 36-months post-transplant (6% vs. 9%, 10% vs. 13%, and 18% vs. 15%, respectively).

• Late acute rejection was numerically more common with alemtuzumab (10% vs. 2%; p=NS)• The composite endpoint of freedom from rejection, graft loss or death was similar between both agents.• SAFETY: overall, more infectious disease seen with rATG, but similar rates of serious infectious complications.

• This study was likely underpowered to detect a difference in late rejection among the individual groups.

Hanaway MJ, et al. N Engl J Med 2011;364:1909-19

Biologic Agent Overview

Clinical Use

Agent Class Induction Treatment Cost

Basiliximab Anti-CD25

Antibodies

(non-

depleting)

20 mg =

$4719.29

Alemtuzumab Anti-CD52

Antibody

(depleting)

30 mg =

FREE

e-ATG/r-ATG Polyclonal

Antibodies

(depleting)

1.5 mg/kg

x 70 kg =

$4635.75

Poll Question:

• Continuation of Induction Case:

• Nadir SCr was 1.93 at 3 month post-txp

• Renal biopsy showed severe arteriosclerosis that may explain why his SCr remains high.

• TAC 8-10 ng/dl before the biopsy; TAC goal of 6-8 ng/dl since the biopsy

• MPA 720 mg BID; no corticosteroids

• What would you do with Maintenance Immunosuppression:

1. Continue the current immunosuppression course

2. Drop TAC goal to 4-6 ng/dl and add back in 5 mg of Prednisone

3. Convert patient from TAC to Everolimus

4. Convert patient from TAC to Belatacept

Maintenance Immunosuppression

• Calcineurin Inhibitors (CNI)• Cyclosporine (Sandimmune® / Neoral® /

Gengraf®)• Tacrolimus (Prograf® / Astagraf XL® /

Envarsus XR®)

• Inhibitors of T-cell Proliferation• Azathioprine (Imuran®)• Mycophenolate mofetil (CellCept®)• Enteric-Coated Mycophenolic Acid

(Myfortic®)

• Mammalian Target of Rapamycin (mToR) Inhibitors

• Sirolimus (Rapamune®)• Everolimus (Zortress®)

• Co-Stimulation Blockade• Belatacept (Nulojix®)

• Non-specific immunosuppressants• Corticosteroids

Primary agent Tertiary agentSecondary agent

CsA

TAC

Sirolimus

Everolimus

Belatacept

AZA

MMF

EC-MPA

Sirolimus

Everolimus

Prednisone

AZA = azathioprine, CSA = cyclosporine, EC-MPA=enteric-coated mycophenolate sodium, MMF = mycophenolate mofetil, TAC = tacrolimus

Common Combinations of Immunosuppressive Regimens

Understanding CsA and TAC


Calcineurin Inhibitors: CsA and TAC

Numerous studies have compared efficacy and side-effects.

in general (though there is some variation between studies):

Efficacy

• Patient and allograft survival has been similar for the 2 CNIs

• Acute rejection rates are reduced with TAC

Safety/tolerability

• CsA has been associated with greater increases in lipid levels and blood pressure

• TAC has been associated with greater incidence of new-onset posttransplant diabetes and neurologic adverse events

• Each has drug-specific side-effects

Calcineurin Inhibitors: CsA and TAC

• Dosing:• Due to significant inter- and intra-patient variability, therapeutic drug monitoring (TDM) is employed to

maximize the efficacy of both CNIs.• CsA and TAC: overall exposure is best correlated to C0 levels

• Appropriate levels are dependent on institution-specific protocols and concomitant immunosuppressants

• DDI: both agents are substrates for CYP3A4 and P-gp

• Pricing:• CsA: 25 mg capsule = $3.33; 100 mg capsule = $11.17• CsA Modified: 25 mg capsule = $1.38; 100 mg capsule = $5.50• TAC: 0.5 mg capsule = $2.23; 1 mg capsule = $4.46; 5 mg capsule = $22.30• TAC once-daily:

• Astagraf XL: 0.5 mg capsule = $2.83; 1 mg capsule = $5.65; 5 mg capsule = $28.26• Envarsus XR: 0.75 mg tablet = $4.36; 1 mg tablet = $5.82; 4 mg tablet = $23.28

CNI Adverse Events

• Cardiovascular – Hypertension; Hypercholesterolemia

• Glucose intolerance

• Neurotoxicity – Tremor; Headache; Insomnia; Paresthesia

• Nephrotoxicity – perhaps long-term dose and level-related

• Malignancy – related to overall immunosuppression

• Physical – Gingival Hypertrophy; Hirsutism (CSA); Alopecia (TAC)

IR Tac (Prograf) vs. Tac-ER (Astagraf XL) vs. LCP-Tac (Envarsus XR)

• Both TAC-IR and TAC-ER exhibited similar PK profiles with higher peak concentrations, shorter time to Tmax, and higher peak-trough ratio compared with LCP-TAC when normalized for AUC

Tremblay S, et al. American Journal of Transplantation. 2017;17(2):432-442.

Bunnapradist S, et al. Transpl Int 2016;29(5):603-11

In favor of TAC-IRIn favor of LCP-Tacro

TAC-IR (n=49)

36


Please see Full Prescribing Information, including Boxed Warning.

LCP-Tacro (n=44)


1 Year Outcomes in African-Americans from Two Phase 3 Trials

TAC-IR (n=52)

37Please see Full Prescribing Information, including Boxed Warning.


LCP-Tacro (n=32)


Efficacy in Patients >65 Years

Langone A, et al. Clinical Transplantation2015;29(9):796-805

a

• 78.9% of patients and 86.8% of physicians reported an improvement after

switching to LCP-Tacro(P < 0.0005 and P < 0.0001, respectively)

Mycophenolic Acid (MPA): MMF and EC-MPA

• Inhibit lymphocyte proliferation

• Inhibitors of purine and DNA synthesis• cells other than lymphocytes have an alternate

synthesis pathway

• thus, selective antiproliferative effect on T and B cells

MPA: MMF and EC-MPA

• Dosing:• MMF: 1 g BID• EC-MPA: 720 mg BID

• TDM is not routinely recommended

• DDI: divalent/trivalent cation-containing antacids and supplements, cyclosporine• MMF only appears to interact with proton pump inhibitors1

• Pricing:• MMF: 1 g = $15.85• EC-MPA: 720 mg = $21.93

• ADR: • Myelosuppression• Gastrointestinal disorders, both upper and lower GI tract• Associated with significant teratogenic effects (REMS program with all MPA products)

1. Ruppercht K, et al. J Clin Pharmacol 2010;49:1196-201

AllograftAzathioprine

6-mercaptopurine

Thioinosinic acid(TIMP)

T

Allograft

BM

B

Promyelocyte

Anemia B, T Cell

Proliferation MonocytopeniaThrombocytopenia

Purine synthesis

Thioguanylic acid

Thiodeoxyguanosinetriphosphate

No DNASynthesis

• AZA is a prodrug of 6-MP. • 6-MP is incorporated into DNA where it inhibits purine synthesis and prevents the

formation of RNA.• Inhibits gene replication and subsequent activation of T-cells.

AZA

AZA

• Dosing: 1 - 3 mg/kg/day, titrated to hematological effects

• DDI: allopurinol, febuxostat

• Pricing:• 50 mg = $2.11

• ADR: • Myelosuppression• RARE: pancreatitis

mToR Inhibitors: Sirolimus and Everolimus• Both agents binds to FKBP, but do

not inhibit calcineurinphosphatase

• The sirolimus or everolimus/ FKBP complex inhibits mToR, a driver of cell proliferation

• This inhibition results in a reduction in IL-2 driven lymphocyte proliferation

• Everolimus is a derivative of Sirolimus with slightly different PK parameters.


Molecular Inhibition of G1 → S ProgressionConsequences

Biological Down-Regulation of ProliferationConsequences

Cellular T Cells B Cells Smooth EndothelialTargets Muscle Cells

• Incidence of Acute Rejection Episodes

• Risk of Chronic Allograft Nephropathy

• Requirement for Calcineurin Inhibitors

• Wound Healing / Anti-Cancer Effects

ClinicalConsequences

Understanding the impact of the mToRInhibitors

mToR Inhibitors: Sirolimus and Everolimus

• Dosing:• TDM (C0 levels) is employed to maximize the

efficacy of both mToR inhibitors• Appropriate levels are dependent on institution-

specific protocols and concomitant immunosuppressants

• Common Doses• Sirolimus: 1 – 2 mg QD

• Everolimus: 0.75 – 2.25 mg BID

• DDI: both agents are substrates for CYP3A4 and P-gp

• Pricing:• Sirolimus:

• 0.5 mg tablet = $8.47• 1 mg tablet = $16.95• 2 mg tablet = $31.50

• Everolimus: • 0.75 mg tablet = $30.46

• ADR: • Cardiovascular (hypercholesterolemia,

hypertriglyceridemia)• Myelosuppression• Dermatologic (rash, mouth ulcers)• Musculoskeletal (myalgias, muscle

weakness)• Interstitial pneumonitis• Renal (proteinuria)

• General precaution not to use in patients with a SCr > 2 mg/dl and/or > 500 mg of proteinuria

• Hepatotoxicity• Decreased wound healing

Co-Stimulation Blockade: Belatacept• Belatacept is a fusion protein that acts as a selective T-cell costimulation

blocker by binding to CD80/86 receptors on APCs and blocking the required CD28 mediated interaction between APCs and T-cells needed to activate the T-cells.

Belatacept


Co-Stimulation Blockade: Belatacept

• Dosing:• Initial Phase: 10 mg/kg/dose on Days 1

(day of transplant, prior to implantation), and 5, then again at Week 2, 4, 8 and 12.

• Maintenance Phase: 5 mg/kg/dose every 4 weeks (+ 3 days) beginning at Week 16

• DDI: none reported

• Pricing:• 250 mg = $1135.46

• 5 mg/kg x 70 kg = $2270.92 (must use 2 vials)

• ADR: • Cardiovascular (edema)

• CNS(fever, HA, insomnia)

• GI (diarrhea, constipation, nausea, abdominal pain)

• GU (UTI)

• Hemataologic (myelosuppression)

• Musculoskeletal (arthralgias)

• Respiratory (cough, dyspnea)

Belatacept Conversion

• Belatacept dosing: 5 mg/kg IV on days 1, 15, 29, 43 and 57, followed by an infusion every 28 days thereafter.

• CNI or mToR dose to be tapered• Week 1: 100%

• Week 2: 75%

• Week 3: 50%

• Week 4: 25%

• Week 5: STOP


Early Conversion - Elhamahmi, et al. Transplantation 2017.• Single-center, retrospective case control study.

• Patients were convereted to belatacept if they had a stable but low GFR and they were at least 1-month posttransplant.

• 30 patients were converted with 30 direct matched controls. • Median pre-conversion eGFR for the entire cohort was 23.0

ml/min/1.73m2.

• The delta eGFR was 11.0 ml/min/1.73m2 in belatacept group and 4.8 ml/min/1.73m2 in the control group (p=0.045).

• Acute rejection post-conversion occurred in 5 (16.7%) in the conversion group and none of the control group (p=0.052).

• The authors concluded that early belatacept conversion in kidney transplant recipients with stable low eGFR may only result in a modest increase in GFR.

Early Conversion - Nair, et al. Clinical Transplantation 2017.• Single-center, retrospective analysis.

• Patients converted to belatacept if they had delayed graft function or poor baseline renal function (eGFR <30 mL/min/1.73m2) < 6 months post-transplant.

• 16 patients were converted, with 12 due to DGF.• Patient survival was 100%, and graft survival was 88%.

• The mean creatinine fell from 3.9±1.82 mg/dL pre-conversion to 2.1±1.1 mg/dL at 6 months and 1.9±0.47 mg/dL at 12 months post-conversion.

• There was no significant increased risk of rejection, infection, or malignancy.

• The authors concluded that belatacept conversion in patients with DGF or slow graft function is safe and efficacious.


Early Conversion - Wojciechowski, et al. Clinical Transplantation 2017.• Single-center, retrospective case control study.

• Patients converted to belatacept if they had delayed graft function.

• 20 patients were converted • The mean eGFR on the day of belatacept conversion was 16 (SD 12.7)

mL/min/1.73m2 and rose to 43.1 (SD 15.8) mL/min/1.73m2 at 30 days post-conversion (P<.0001).

• The acute rejection rate was 20% with 100% patient survival at 12 months post-transplant.

• There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy.

• The authors concluded that belatacept conversion for prolonged DGF resulted in an improvement in eGFR.

Late Conversion - Schulte, et al. Journal of Nephrology 2017.• Single-center, retrospective analysis.

• Patients converted to belatacept if they had tacrolimus intolerance (n=14) or marginal transplant function (n=6).

• 20 patients were converted• Conversion to belatacept = 28.8 months post-

transplant.

• Mean eGFR before conversion was 22.2 ± 9.4 ml/min /1.73m2 at baseline and improved significantly to 32.1 ±12.6 ml/min/1.73m2 at 12 months after conversion.

• Serum bicarbonate significantly increased from 24.4 ±3.2 mmol/l at baseline to 28.7 ± 2.6 mmol/l after 12 months.

• Conversion to belatacept decreased parathyroid hormone and phosphate concentrations significantly, whereas albumin levels significantly increased.

• Two acute rejections after conversion.

• No increase in infectious or malignant side effects.


European Experience - Darres, et al. Transplantation 2018.• Multi-center, retrospective study.

• 219 patients converted to belatacept post-transplant, mainly due to renal impairment.

• Mean conversion date was 21.2 months post-transplant

• 32 patients were converted within 3 months of transplant

• Overall:• Mean eGFR rate increased from 32 ± 16.4 at baseline to 38 ± 20

ml/min/1.73m2.• 18 patients (8.2%) presented with an acute rejection episode after

conversion; 3 developed a donor-specific antibody. • Conversion to belatacept before 3 months posttransplantation was the

main predictive factor for a significant increase in eGFR.• The authors concluded that belatacept conversion was effective and safe.

Corticosteroids

• The exact MOA is still not fully understood. Some believe…• High dose: > 100 mg of prednisone equivalents.

• MOA = directly toxic to T cells• Low dose: < 100 mg of prednisone equivalents.

• nonspecific immunosuppressive agents - inhibit IL-1, IL-2, IL-3, IL-6, IL-15, TNF-alpha and INF-gamma at low doses.

• Decreased activation of T cells.• What we do know:

• Blockade of Cytokine Gene Expression• ↓ T-cell and APC cytokine expression

• Bind to heat shock protein → translocates to nucleus → binds to GRE → inhibits transcription of cytokine genes → inhibition of IL-1, IL-2, IL-3, IL-6, INF-γ, and TNF-α

• ↓ cytokine-receptor expression• Nonspecific Effects

• Antiinflammatory effects

Corticosteroids

• Dosing: doses vary widely from institution to institution.

• Highest doses at time of transplant or as treatment of an acute rejection episode.

• DDI: CYP - 450 inducer (dexamethasone) and inhibitor (methylprednisolone).

• Pricing:• 5 mg tablet = $0.23

• ADR: • Cardiovascular (hypertension,

hyperlipidemia)• Endocrine (hyperglycemia)• CNS (mood changes, anxiety)• Osteoporosis• Weight gain• Edema• Lipodistrophy

Current Trends in Maintenance Immunosuppression in Kidney Transplantation

Hart, et al. American Journal of Transplantation 2021;21(s2):21-137.

Treatment of Cellular Rejection

• Acute cellular rejection is most common during the first 6 months posttransplant

– Becomes substantially less common over time

• Most episodes are not accompanied by symptoms but present as ↑ serum creatinine level and decreased urine output

• The transplant center should be notified immediately if acute cellular rejection is suspected

• Because treatment is associated with significant side- effects, most suspected acute rejection episodes are biopsied to confirm the diagnosis

Treatment of Cellular Rejection

• First-line therapy is high-dose pulse corticosteroids.

• Antilymphocyte antibodies are generally reserved for corticosteroid-resistant rejection.

• However, antibodies are sometimes used as first-line treatment for patients with histologically or clinically severe rejection.

• Administration of these agents may be done in conjunction with an intensification of maintenance immunosuppression.

Agent Dosage

Corticosteroids ‒ Intravenous methylprednisolone

‒ 125-1000 mg/day x 3-5 days

‒ 3 to 5 mg/kg x 3-5 days

rATG ‒ 1.5 mg/kg/day x 4-14 days

Alemtuzumab ‒ 30 mg IV or SC x 1 dose

1. Kim, et al. Pharmacotherapy 2014;34(7):733-44

Treatment of Antibody-Mediated Rejection

• Antibody- and cellular-mediated rejection can occur independently or co-exist• When antibody-mediated rejection is independent, treatment options include:1

• High-dose IVIg• Rituximab (Rituxan®)• Bortezomib (Velcade®)• Eculizumab (Soliris®)• Plasmapheresis • Plasmapheresis and low-dose IVIg

• When antibody-mediated and cellular-mediated rejection coexist, therapy for each must be utilized

Treatment of Antibody-Mediated Rejection

Agent Dosing MOA Adverse Events Cost

IVIG • Low-dose after PP (10-100 g)

• High-dose alone (2 g/kg)

• Neutralizes circulating autoantibodies

• Promotes down-regulation of antibody production

• Infusion-related reactions • Mental status changes• Renal dysfunction

• 10 g = $1598.88• 2 g/kg =

$22,384.32

Rituximab • 375 mg/m2

• 1000 mg• Anti-CD20 monoclonal antibody

that induces B-cell destruction through complement dependent cytotoxicity

• Infusion-related reactions • Infection• Mucocutaneous reactions

(i.e., SJS)• Myelosuppression

• 375 mg/m2 (1.73 m2) = $7032.45

• 1000 mg = $10,840.00

Bortezomib • 1.3 mg/m2 on Days 1, 4, 7, 10

• Proteasome inhibitor that induces cell-cycle arrest and apoptosis of plasma cells

• Myelosuppression• Neuromuscular (neuropathy,

myalgias)

• One cycle (4 doses) = $7694.32

Eculizumab • 1200 mg x 1• 900 mg weekly x 4

doses• 1200 mg at week 5

• monoclonal antibody that inhibits its cleavage of C5 to C5a and C5b,thus preventing the generation of the MAC

• Infection (risk for meningococcal infection –REMS)

• 1200 mg = $31,310.40

Kim, et al. Pharmacotherapy 2014;34(7):733-44

Summary

Despite some some newer options for induction (i.e., alemtuzumab) and maintenance (i.e., belatacept, everolimus) therapy, there have been little improvement in short- and long-term outcomes in renal transplantation in the past 5-10 years.

Proliferation of available immunosuppressants should allow for streamlining of immunosuppressive regimen to create more personalized medicine.

Major focus of current clinical research is improving long-term outcomes, in particular, increasing patient and graft survival, and decreasing morbidity.

Question 1

• The following best describes the mechanism of action of which immunosuppressant: a chimeric, monoclonal antibody that competitively inhibits the activation of T lymphocytes by blocking the IL-2 receptor.

A. Basiliximab

B. Prednisone

C. Alemtuzumab

D. Antithymocyte Globulin Rabbit

E. Tacrolimus

Question 1

• The following best describes the mechanism of action of which immunosuppressant: a chimeric, monoclonal antibody that competitively inhibits the activation of T lymphocytes by blocking the IL-2 receptor.

A. Basiliximab is an IL-2 receptor antagonist and blocks cellular proliferation

B. Prednisone

C. Alemtuzumab

D. Antithymocyte Globulin Rabbit

E. Tacrolimus

Question 2

• Therapeutic drug monitoring (TDM) is commonly used in renal transplant to manage pharmacotherapy. Which of the following immunosuppressants does NOT require TDM.

A. Tacrolimus

B. Everolimus

C. Cyclosporine

D. Belatacept

E. Sirolimus

Question 2

• Therapeutic drug monitoring (TDM) is commonly used in renal transplant to manage pharmacotherapy. Which of the following immunosuppressants does NOT require TDM.

A. Tacrolimus

B. Everolimus

C. Cyclosporine

D. Belatacept - the CNI and mToR inhibitors require TDM. TDM is not necessary when managing a patient receiving belatacept.

E. Sirolimus

References

• Halloran PF. Immunosuppressive drugs for kidney transplantation. New England Journal of Medicine 2004;351:2715-29.

• Gabardi S, Martin S, Roberts K, Grafals M. Induction immunosuppressive strategies in renal transplantation. American Journal of Health-System Pharmacists 2011;68:211-8.

• Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. American Journal of Health-System Pharmacists 2012;69:1961-75.

• Kim M, Martin ST, Townsend K, Gabardi S. Antibody mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy 2014;34:733-44.

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Transplant Immunosuppression