title: Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants.
abstract: 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.
authors.affiliation: Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan 48109-1065, USA.
authors.forename: Aline H
authors.initials: AH
authors.lastname: Saad
authors.forename: Daryl D
authors.initials: DD
authors.lastname: DePestel
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Carver
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001393:Azoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001693:Biological Transport, Active; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D004790:Enzyme Induction; D004794:Enzyme Repression; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D016377:Organ Transplantation; D011110:Polymorphism, Genetic
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D001393:Azoles; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human