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Factors Influencing the Magnitude and Clinical Significance of Drug Interactions Between Azole Antifungals and Select Immunosuppressants

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Factors Influencing the Magnitude and Clinical Significance of Drug Interactions Between Azole Antifungals and Select Immunosuppressants Factors Influencing the Magnitude and Clinical Significance of Drug Interactions Between Azole Antifungals and Select Immunosuppressants Aline H. Saad, Pharm.D., Daryl D. DePestel, Pharm.D., and Peggy L. Carver, Pharm.D. The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians’ attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P- glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations. Key Words: drug interactions, azole antifungals, immunosuppressants, ketoconazole, itraconazole, fluconazole, voriconazole, cyclosporine, tacrolimus, sirolimus. (Pharmacotherapy 2006;26(12):1730–1744) OUTLINE Active Transport of Azoles and Mechanisms of Drug Interactions Mediated by Immunosuppressants Cytochrome P450 Enzymes and Transport Proteins Enzyme-Transporter Cooperativity Metabolism Involving the Cytochrome P450 Inhibition Constant Enzyme System Metabolism of Azoles Substrates, Inducers, and Inhibitors Metabolism of Cyclosporine, Tacrolimus, and Genetic Polymorphism Sirolimus From the Department of Pharmacy Services, University of Drug Interactions Between Azoles and Cyclosporine Michigan Health System, Ann Arbor, Michigan (all authors); Ketoconazole and the Department of Clinical Sciences, College of Fluconazole Pharmacy, University of Michigan, Ann Arbor, Michigan (all Itraconazole authors). Voriconazole Address reprint requests to Peggy L. Carver, Pharm.D., College of Pharmacy, University of Michigan, 428 Church Posaconazole Street, Ann Arbor, MI 48109-1065; e-mail: [email protected]. Drug Interactions Between Azoles and Tacrolimus AZOLE-IMMUNOSUPPRESSANT DRUG INTERACTIONS Saad et al 1731 Ketoconazole undergoing solid organ transplantation, the 1–6- Fluconazole month period after the procedure is highlighted Itraconazole by the emergence of opportunistic infections, Voriconazole such as histoplasmosis, coccidioidomycosis, Posaconazole blastomycosis and Pneumocystis carinii Drug Interactions Between Azoles and Sirolimus (Pneumocystis jiroveci) pneumonia.6 Patients Ketoconazole receiving bone marrow transplantation are at Fluconazole highest risk for fungal infections during the Voriconazole preengraftment period, which lasts from the day Other Azoles bone marrow or stem cells are infused (day 0) to Effect of Intravenous versus Oral Administration on approximately day 30 after transplantation.4 Drug Interactions Between Immunosuppressants and Given the high mortality rate associated with Azoles invasive mycoses in solid organ or bone marrow Recommendations for the Clinical Management of transplantation, effective prophylaxis and Drug Interactions Between Immunosuppressants and treatment of such infections are worthy goals. Azoles Although appropriate antifungal agents and their Additional Factors Affecting Drug Interactions dosages for treating opportunistic mycoses have Advantages of Drug Interactions been defined, decisions regarding the modes of Drug Interactions Between Azoles and Investigational drug delivery, the patients who should receive Immunosuppressants antifungal prophylaxis, the duration of treatment Conclusion or prophylaxis, and the potential for the emergence of resistant fungi remain subjects of The frequency of infections and mortality due 7 to mycotic disease in the United States has uncertainty and controversy. increased dramatically over the past 2 decades. Investigators have described the need to design Among infectious disease–related deaths, those a therapeutic prescription for transplant due to mycoses increased from being tenth most recipients that prevents and treats the two major common in 1980 to seventh most common in barriers to successful transplantation: rejection 1997.1 Invasive fungal infections particularly and infection. The therapeutic prescription affect immunocompromised patients, including consists of an immunosuppressive program and those with cancer, acquired immunodeficiency an antimicrobial program; changes in the syndrome, or solid organ or bone marrow intensity and nature of one program obligate transplants, as well as certain high-risk patients changes in the other. The technical and/or with burns or critical conditions and neonates anatomic consequences of transplantation, the born prematurely.2, 3 time course of infection after transplantation, and Fungal infections occur in 11–28% of the possibility of drug interactions with the transplant recipients. Although the highest immunosuppressive program greatly influence frequency is reported in liver transplant the use of antimicrobials in transplant recipients.8 recipients, 10–15% of patients undergoing bone Drug interactions between immunosuppres- marrow transplantation become infected, with a sants and azoles are discussed elsewhere.9–12 Our mortality rate of 60–75%.4 The interaction of objective was to describe certain studies to three factors largely determine the high illustrate similarities and differences among these frequency of fungal infections in transplant interactions so that clinicians can appreciate and recipients: technical and/or anatomic abnor- apply these findings in an individualized patient malities, intensity of environmental exposure, approach rather than follow only the one-size- and the patient’s net state of immuno- fits-all dosing recommendations suggested in suppression.3 many tertiary references. Clinicians must be Fungal infections associated with immuno- aware of the combined influence of drug suppression-related, T cell–mediated defects transport and metabolic routes on the likelihood include mucosal candidiasis, cryptococcosis, and and magnitude of drug interactions. Because mucormycosis, whereas neutropenia-related data are not available for all potential drug-drug fungal infections include aspergillosis and combinations, a thorough understanding of the disseminated candidiasis.4 These infections tend principles underlying drug interactions is crucial to occur early after transplantation, and their to anticipate potential interactions with new or frequency decreases over time.5 In patients existing agents used in the clinical setting. 1732 PHARMACOTHERAPY Volume 26, Number 12, 2006 Mechanisms of Drug Interactions Mediated by pass elimination results in variable (often low) Cytochrome P450 Enzymes and Transport oral bioavailability of CYP3A4-metabolized Proteins drugs. An important characteristic of CYP3A is its Metabolism Involving the Cytochrome P450 large interindividual variability in activity, which Enzyme System reflects a genetic effect combined with modula- A thorough understanding of the mechanisms tion by environmental factors. The inhibition of drug interactions provides clinicians the ability and induction of enzymes often substantially to predict such interactions and to devise increases this variability. Hepatic CYP3A4 varies strategies to minimize or avoid those of greatest at least 20-fold, and enteric CYP3A4 varies 10- clinical significance.13 Drug interactions can be fold among individuals. However, the CYP3A4 categorized as pharmacodynamic or pharmaco- content of each site appears to be regulated kinetic. Pharmacodynamic interactions include independently. Thus, one patient might have additive, synergistic, or antagonistic interactions high CYP3A4 activity in the liver and low that can affect efficacy or toxicity. Pharmaco- CYP3A4 activity in the intestine, whereas another kinetic interactions result when one drug alters patient has the opposite activities; the liver is the the absorption, distribution, metabolism, or major site of drug metabolism in the first patient, excretion of another drug. whereas the intestine is the major site in the Inhibition or induction of hepatic and second.18 Relative contributions of hepatic and extrahepatic cytochrome P450 (CYP) enzymes is enteric metabolism can be estimated separately the most common mechanism of drug by determining differences in drug clearance after interactions.13 The major site of drug metabolism oral and intravenous administration of a is the liver, where two types of reactions occur. CYP3A4-metabolized drug.17 In phase I reactions catalyzed by CYP enzymes, The CYP group of enzymes can be highly oxidation of a parent drug yields a more polar, substrate specific and therefore capable of hydrophilic moiety that may be pharmaco- metabolizing only a few
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