Download Drug Interaction with Immunosuppressants

Drug Interaction with Immunosuppressants
A Case Report and Review
Immunospuppression in transplantation
Aim of immunosuppression:
Prevent acute rejection, while avoiding infection and toxicity.
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.
Calcineurin inhibitor (CNI)
Cyclosporin: cyclic peptide
Tacrolimus: macrolide
Anti-metabolites
Azathioprine
Mycophenolate mofetil (MMF)
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:
hypercholesterolaemia
infection
acne
mouth ulcers
pneumonitis
gastrointestinal side effects
wound dehiscence
Nephrotoxicity, neurotoxicity, hypertension
and glucose intolerance are not usually observed.
Case Report
Age: two year-old
Sex: 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
-3 weeks: routine echocardiography and EMBx were normal.
Day -2 to day 0: recurrent fever with no focus
progressive anemia
renal dysfunction in a local hospital.
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.
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 of
therapy 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?
1. Narrow therapeutic index
Therapeutic index = toxic dose/minimal effective dose
graft rejection
adverse effects
Desirable pharmacological effect only within narrow
ranges of concentration in the blood.
2. Poor dose response relationship
Highly variable absorption, distribution and metabolism
between and within patients.
Poor solubility in water
Drug-drug interaction
Polymorphism or defectiveness in key enzymes responsible for
metabolizing immunosuppressants .
3. The clinical effect is difficult to measure
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.
Common medications taken by transplant recipients
Immunosuppressants
Antidepressants
Antimicrobials
Cholesterol-lowering Agents
Antihypertensives
Anti-ulcer Medications
Drug-drug interactions
pharmacodynamic
pharmacokinetic
Pharmacodynamic interactions
Drug-drug interactions that modulate the drug's effect
in the absence of a corresponding change in plasma
concentration.
Examples include interactions at the level of receptor binding or
secondary messenger systems.
For example, an increase in renal toxicity is observed with the coadministration of naproxen and CsA.
Pharmacokinetic interactions
Drug-drug interactions that alter the plasma concentration of 1
or both drugs.
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
???
UDP-glucuronosyltransferases (UTGs)
in MPA Metabolism
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).
Xanthine oxidase in AZA Metabolism
AZA  6-mercaptopurine  inactivation by xanthine oxidase
allopurinol inhibits xanthine oxidase, co-administration of
allopurinol and azathioprine can result in increased levels of 6mercaptopurine.
CYPs
The most prominent family of drug-metabolizing enzymes.
Inducers
Active drug
Activators
CYP3A
Inhibitors
Inactive drug
Substrates
Drug transporters and Immunosuppressant
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)
CYP3A and P-gp Substrates (S), Inhibitors (I), Inducers(In), and Activators (A)
CYP3A
Immunosuppressants
Cyclosporine (S, I)
Methylprednisolone (I)
Sirolimus (S, I)
Tacrolimus (S)
P-gp
Cyclosporine (S, I, In)
Methylprednisolone (S)
Prednisolone (S, In)
Sirolimus (I, In)
Tacrolimus (S, I, In)
Antibiotics/antifungal agents Clarithromycin (S)
Clotrimazole (I)
Erythromycin (S, I)
Itraconazole (S, I)
Ketoconazole (S, I)
Clarithromycin (I)
Clotrimazole (In)
Erythromycin (S, I, In)
Itraconazole (S, I)
Ketoconazole (I)
Sparfloxacin (S)
Antihistamines
Astemizole (I)
Chlorpromazine (I)
Cimetidine (S)
Fexofenadine (S)
Ranitidine (S)
Astemizole (S, I)
Cimetidine (I)
Loratidine (S)
Terfenadine (PS, I)
CYP3A
P-gp
Psychoactive agents/anticonvulsants
Amitriptyline (S)
Carbamazepine (In)
Midazolam (I, In)
Nefazodone (I)
Nortriptyline (S)
Phenobarbital (In)
Phenytoin (S, In)
Amitriptyline (S)
Midazolam (S, I)
Nefazodone (S, I)
Phenobarbital (In)
Hormonal agents
Cortisol (S)
Dexamethasone (S, I)
Estradiol (S, I)
Hydrocortisone (S)
Progesterone (S, I)
Testosterone (S, A)
Aldosterone (S)
Cortisol (I)
Dexamethasone (S, In)
Estradiol (In, MS)
Hydrocortisone (S, I)
Insulin (In)
Progesterone (I)
Testosterone (I)
Other cytotoxics
Colchicine (S)
Colchicine (S, In)
Mitoxantrone (S, In)
CYP3A
P-gp
Cardiac agents
Amiodarone (S)
Atorvastatin (S)
Digitoxin (PS)
Diltiazem (S, I)
Felodipine (S)
Fluvastatin (S)
Lidocaine (S)
Lovastatin (S)
Nicardipine (S, I)
Nifedipine (S, I)
Nitrendipine (S, I)
Pravastatin (S)
Quinidine (S, I)
Simvastatin (S)
Verapamil (S, I)
Amiodarone (I, In)
Atorvastatin (I)
Celiprolol (S)
Digoxin (S)
Diltiazem (S, I, In)
Felodipine (I)
Lidocaine (I)
Nicardipine (I, In)
Nifedipine (In)
Nitrendipine (I)
Quinidine (S, I)
Talinolol (S)
Terfenadine (I)
Verapamil (S, I, In)
HIV agents
Amprenavir (S, I)
Indinavir (S, I)
Nelfinavir (S, I)
Ritonavir (S, I)
Saquinavir (S, I)
Amprenavir (S, In)
Indinavir (S)
Nelfinavir (S, I, In)
Ritonavir (S, I, In)
Saquinavir (S, I)
CYP3A
Anticancer drugs
Busulfan (S)
Docetaxel (S)
Doxorubicin (S)
Etoposide (S)
Paclitaxel (S)
Tamoxifen (S)
Vinblastine (S, I)
Vincristine (S, I)
Vindesine (S)
Benzodiazepines
Alprazolam (A)
Clonazepam (S)
Midazolam (S)
Triazolam (S)
P-gp
Actinomycin D (S)
Cisplatin (S, In)
Cytarabine (S)
Daunorubicin (S, In)
Docetaxel (S)
Doxorubicin (S, In)
Etoposide (S, In)
Fluorouracil (S, In)
Methotrexate (S, In)
Mitomycin (S)
Paclitaxel (S)
Taxol (S)
Tamoxifen (I, In)
Vinblastine (S, I, In)
Vincristine (S, In)
Vindesine (S)
CYP3A
P-gp
Opiates
Methadone (S, I)
Fentanyl (S)
Loperamide (S)
Methadone (S, I)
Morphine (S, In)
Others
Grapefruit juice (I)
Losartan (S)
St. John's wort (In)
Bepridil (I)
Bromocriptine (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)
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.
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.
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.
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.