Drug Interaction with ImmunosuppressantsA Case Report and Review

Aim of immunosuppression: Prevent acute rejection, while avoiding infection and toxicity.

Immunospuppression in transplantation

The primary efficacy end-points of immunosuppression:The incidence of clinical or biopsy-proven acute rejection in the first six months or one year. Graft survival and patient survival are also reported.

Secondary end-points of immunosuppression:The incidence of side-effects, such as infection, renal dysfunction, diabetes, and lymphoproliferative disease.

Azathioprine

Mycophenolate mofetil (MMF)

Anti-metabolites

Calcineurin inhibitor (CNI) Cyclosporin: cyclic peptide

Tacrolimus: macrolide

Glucocorticoids Methylprednisolone

Prednisolone

TOR inhibitors Sirolimus: macrolide

Everolimus

ATG (anti-thymocyte globulin) or interleukin-2 receptor antagonists, such as basiliximab or daclizumab

The combinations of drugs and variations in the doses, formulations, timing, and weaning schedules are almost endless.

Adverse Effects of Immunosuppressants

1. the toxicity resulting from over-immunosuppression (eg, infection)

2. Drug-specific adverse reactions.

Side effects of TOR inhibitors

The main side effects are: hypercholesterolaemiainfectionacnemouth ulcerspneumonitisgastrointestinal side effects wound dehiscence

Nephrotoxicity, neurotoxicity, hypertensionand glucose intolerance are not usually observed.

Age: two year-oldSex: female ABO-incompatible heart transplantation at four months of age.

Maintenance immunosuppression included:tacrolimus (FK506) 0.8 mg p.o. q12 h mycophenolate mofetil 100 mg p.o. q12 h.prednisolone

Case Report

Day 1: Transfered to HSC signs of congestive heart failure. ECG revealed ischemic changes. decreased LVEF with dilatation and severe right ventricular

dysfunction. One small arterial vessel exhibited intimal hyperplasia consistent with CAD.

Liver transaminases were mildly elevated (AST 69 umol/L, ALT 49 umol/L). INR was 1.64 and albumin was 24 g/L. Hemoglobin was low (72 g/ L) Renal dysfunction progressed.The patient was transfused with packed red blood cells.

(Normalized hemoglobin)Methylprednisolone and Thymoglobulin® was discontinued. The patient was re-listed for another heart transplant.

-3 weeks: routine echocardiography and EMBx were normal.

Day -2 to day 0: recurrent fever with no focus progressive anemiarenal dysfunction in a local hospital.

Day 2 to 6: Tacrolimus was held on day 2 for five days because of a reported trough blood concentration >30 ug/L [EMIT immunoassay, Viva Analyzer (Dade Behring, Deerfield, IL, USA)].

The patient required one-fourth of her pre-admission maintenance dose (0.02 mg/kg/day orally) to keep trough concentrations within the target range of 8–10 ug/L. Potential influencing factors such as liver dysfunction, decreased enteral intake (resulting in increased tacrolimus absorption) and drug interaction (concomitant pulse methylprednisolone) resulting in decreased calcineurin inhibitor metabolism and excretion were present.

Day 5: Liver transaminases had normalized. Albumin was 27 g/L.

Day 7: Nadolol and amiodarone were prescribed on day 7 to control arrhythmia.

Day 8: Tacrolimus trough concentrations reported day 8 and day 10 were within the target range.

Day 10: Conjugated bilirubin was zero and the unconjugated fraction was eight.

Day 11: Sirolimus was prescribed on day 11 in an attempt to augment immunosuppression yet spare calcineurin inhibitor exposure given the patient’s renal dysfunction. The initial dose of 1 mg p.o. daily (0.06 mg/kg/day) was low in relation to our centre’s experience with children in this age group.

Day 13: Given that tacrolimus was to be discontinued, sirolimus was then increased to 2 mg p.o. daily (0.12 mg/kg/day).

Day 16: Sirolimus was held. The target trough concentration was 10 ug/L. The trough concentration (Ultima Tandem Mass Spectrometer, Waters Ltd., Centennial Park, Elstree, Hertfordshire, UK) was 52.7 ug/L. Tacrolimus was discontinued. Trough concentration was 12.9 ug/L

Day 17-30: Sirolimus blood concentrations remained above the target range for an additional 14 days.

Day 31: Once the trough concentration normalized, sirolimus was restarted at a smaller dose 0.5 mg p.o. daily (0.03 mg/kg/day).

Day 32: The dose was further decreased to 0.3 mg p.o.daily (0.02 mg/kg/day). trough concentration = 17.2 ug/L.

Day 37: The trough blood concentration was measured after five days oftherapy and was reported as 13.4 lg/L, still above the target concentration.

Day 42: The patient succumbed because of complications of ECMO.

Triglycerides and cholesterol were not measured during the hospital course; however, blood samples were intermittently reported as lipemic.

Amiodarone serum concentrations were not analyzed.

Why immunosuppressants needs to be monitored?

Desirable pharmacological effect only within narrow ranges of concentration in the blood.

1. Narrow therapeutic index

Therapeutic index = toxic dose/minimal effective dose

graft rejection adverse effects

Poor solubility in water

2. Poor dose response relationship

Polymorphism or defectiveness in key enzymes responsible for metabolizing immunosuppressants .

Highly variable absorption, distribution and metabolism between and within patients.

Drug-drug interaction

Graft rejection may be the first indication of therapeutic ineffectiveness.

The major adverse effect of the drug is hard to distinguish from a lack of therapeutic effects.

3. The clinical effect is difficult to measure

Common medications taken by transplant recipients

Immunosuppressants

Antimicrobials

Anti-ulcer MedicationsAntihypertensives

Cholesterol-lowering Agents

Antidepressants

pharmacodynamic pharmacokinetic

Drug-drug interactions

Examples include interactions at the level of receptor binding or secondary messenger systems.

For example, an increase in renal toxicity is observed with the co-administration of naproxen and CsA.

Pharmacodynamic interactions

Drug-drug interactions that modulate the drug's effect in the absence of a corresponding change in plasma concentration.

Drug-drug interactions that alter the plasma concentration of 1 or both drugs.

Pharmacokinetic interactions

Drug-metabolizing enzymes

Drug transporters

Common Enzymes Involved in Immunosuppressant Metabolism

Cytochrome P450s (CYPs), ie, 3A4/5,

CsA, SIR, and TAC

UDP-glucuronosyltransferases (UTGs)

MPA

Xanthine oxidase

AZA

Flavin mono-oxygenases, sulfotransferases, and N-acetyl transferases

???

The UGT superfamily is composed of 2 families: UGT1 and UGT2.

Conjugate substrates with the addition of a glucuronyl group.

The rate-limiting step in the metabolism of MPA (active form of MMF).

UDP-glucuronosyltransferases (UTGs) in MPA Metabolism

AZA 6-mercaptopurine inactivation by xanthine oxidase

allopurinol inhibits xanthine oxidase, co-administration of allopurinol and azathioprine can result in increased levels of 6-mercaptopurine.

Xanthine oxidase in AZA Metabolism

The most prominent family of drug-metabolizing enzymes.

CYPs

Active drug Inactive drug CYP3A

Inhibitors

Activators

Substrates

Inducers

Major transporter

P-glycoprotein (P-gp), the protein product of the multidrug resistance 1 gene (MDR1).

CsA and TAC (substrates, inhibtors, inducers).

SIR (inhibtor, inducer)

Other transporters

multidrug resistance gene 2/3,

organic anion transporter proteins

multidrug resistance-related proteins (MRP1-6)

Sister of P-glycoprotein (S-Pgp)

Drug transporters and Immunosuppressant

CYP3A and P-gp Substrates (S), Inhibitors (I), Inducers(In), and Activators (A)

CYP3A P-gp

Immunosuppressants Cyclosporine (S, I) Cyclosporine (S, I, In) Methylprednisolone (I) Methylprednisolone (S) Sirolimus (S, I) Prednisolone (S, In) Tacrolimus (S) Sirolimus (I, In)

Tacrolimus (S, I, In)

Antibiotics/antifungal agents Clarithromycin (S) Clarithromycin (I) Clotrimazole (I) Clotrimazole (In) Erythromycin (S, I) Erythromycin (S, I, In) Itraconazole (S, I) Itraconazole (S, I)Ketoconazole (S, I) Ketoconazole (I)

Sparfloxacin (S)

Antihistamines Astemizole (S, I) Astemizole (I) Cimetidine (I) Chlorpromazine (I) Loratidine (S) Cimetidine (S) Terfenadine (PS, I) Fexofenadine (S)

Ranitidine (S)

CYP3A P-gp

Psychoactive agents/anticonvulsants Amitriptyline (S) Amitriptyline (S) Carbamazepine (In) Midazolam (S, I)Midazolam (I, In) Nefazodone (S, I) Nefazodone (I) Phenobarbital (In) Nortriptyline (S)Phenobarbital (In)Phenytoin (S, In)

Hormonal agents Cortisol (S) Aldosterone (S)Dexamethasone (S, I) Cortisol (I) Estradiol (S, I) Dexamethasone (S, In) Hydrocortisone (S) Estradiol (In, MS) Progesterone (S, I) Hydrocortisone (S, I) Testosterone (S, A) Insulin (In)

Progesterone (I) Testosterone (I)

Other cytotoxics Colchicine (S) Colchicine (S, In)Mitoxantrone (S, In)

Cardiac agents Amiodarone (S) Amiodarone (I, In) Atorvastatin (S) Atorvastatin (I) Digitoxin (PS) Celiprolol (S) Diltiazem (S, I) Digoxin (S) Felodipine (S) Diltiazem (S, I, In) Fluvastatin (S) Felodipine (I) Lidocaine (S) Lidocaine (I) Lovastatin (S) Nicardipine (I, In) Nicardipine (S, I) Nifedipine (In) Nifedipine (S, I) Nitrendipine (I) Nitrendipine (S, I) Quinidine (S, I) Pravastatin (S) Talinolol (S) Quinidine (S, I) Terfenadine (I) Simvastatin (S) Verapamil (S, I, In)Verapamil (S, I)

HIV agents Amprenavir (S, I) Amprenavir (S, In) Indinavir (S, I) Indinavir (S) Nelfinavir (S, I) Nelfinavir (S, I, In) Ritonavir (S, I) Ritonavir (S, I, In) Saquinavir (S, I) Saquinavir (S, I)

CYP3A P-gp

CYP3A P-gp

Anticancer drugs Busulfan (S) Actinomycin D (S)Docetaxel (S) Cisplatin (S, In) Doxorubicin (S) Cytarabine (S) Etoposide (S) Daunorubicin (S, In) Paclitaxel (S) Docetaxel (S) Tamoxifen (S) Doxorubicin (S, In) Vinblastine (S, I) Etoposide (S, In) Vincristine (S, I) Fluorouracil (S, In) Vindesine (S) Methotrexate (S, In)

Mitomycin (S) Paclitaxel (S) Taxol (S)Tamoxifen (I, In)Vinblastine (S, I, In)Vincristine (S, In)Vindesine (S)

Benzodiazepines Alprazolam (A)Clonazepam (S)Midazolam (S)

Triazolam (S)

Opiates Methadone (S, I) Fentanyl (S)Loperamide (S)Methadone (S, I)Morphine (S, In)

Others Grapefruit juice (I) Bepridil (I) Losartan (S) Bromocriptine (In) St. John's wort (In) Chlorambucil (S, In)

Dipyridamole (I) Disulfiram (I)Grapefruit juice (A)Hydroxyurea (S, In)Losartan (S)Octreotide (S)Phenothiazine (I)Probenecid (In)Quinine (I)Reserpine (I, In)Rifampin (In)St. John's wort (In)Tetrabenazine (I)Topotecan (S)Valinomycin (I)Yohimbine (In)

CYP3A P-gp

1: Clin Pharmacokinet. 2006;45(2):169-75. Pharmacokinetic interaction between levofloxacin and ciclosporin or tacrolimus in kidney transplant recipients: ciclosporin, tacrolimus and levofloxacin in renal transplantation.Federico S, Carrano R, Capone D, Gentile A, Palmiero G, Basile V.

2: Transplantation. 2006 Jan 15;81(1):136-7. Interaction between tacrolimus and fumagillin in two kidney transplant recipients.Arzouk N, Michelon H, Snanoudj R, Taburet AM, Durrbach A, Furlan V.

3: Pharmacotherapy. 2006 Feb;26(2):289-95. Links Sirolimus-itraconazole interaction in a hematopoietic stem cell transplant recipient.Said A, Garnick JJ, Dieterle N, Peres E, Abidi MH, Ibrahim RB.

4: Transplantation. 2006 Feb 15;81(3):487-8. Interaction between tacrolimus and omeprazole in a pediatric liver transplant recipient.Moreau C, Debray D, Loriot MA, Taburet AM, Furlan V.

5: J Clin Pharmacol. 2006 Mar;46(3):328-36. Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients.Bergman AJ, Burke J, Larson P, Johnson-Levonas AO, Reyderman L, Statkevich P, Maxwell SE, Kosoglou T, Murphy G, Gottesdiener K, Robson R, Paolini JF.

7: Int J Clin Pharmacol Ther. 2006 Apr;44(4):163-71.Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients.Holdaas H, Hagen E, Asberg A, Lund K, Hartman A, Vaidyanathan S, Prasad P, He YL, Yeh CM, Bigler H, Rouilly M, Denouel J.

6: Biol Blood Marrow Transplant. 2006 Mar;12(3):325-34. Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients.Leather H, Boyette RM, Tian L, Wingard JR.

8: Transplant Proc. 2006 May;38(4):1138-40. Pharmacokinetic interaction between Amprenavir/Ritonavir and FosAmprenavir on cyclosporine in two patients with human immunodeficiency virus infection undergoing orthotopic liver transplantation.Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Motta A, Luzi K, Pecorari M, Gennari W, Masetti M, Gerunda GE, Esposito R.

9: Med Monatsschr Pharm. 2006 May;29(5):179-82. [Interaction between an antiinfective agent and an immunosuppressant after liver transplantation] [Article in German]Swoboda S, Meyer-Massetti C, Hoppe-Tichy T.

10: Clin Pharmacol Ther. 2006 Nov;80(5):509-21. Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients.Naesens M, Kuypers DR, Streit F, Armstrong VW, Oellerich M, Verbeke K, Vanrenterghem Y.

11: Pharmacol Res. 2006 Sep;54(3):181-5. Co-administration of sirolimus alters tacrolimus pharmacokinetics in a dose-dependent manner in adult renal transplant recipients.Baldan N, Rigotti P, Furian L, Margani G, Ekser B, Frison L, De Martin S, Palatini P.

12: Transplantation. 2006 Jun 27;81(12):1750-2. Clinically relevant drug interaction between voriconazole and tacrolimus in a primary renal allograft recipient.Kuypers DR, Claes K, Evenepoel P, Vanrenterghem Y.