Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

Abstract

Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first-or second-line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co-administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft-versus-host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug-drug interactions in these patients. Invasive aspergillosis (IA) is the most common IFD in HSCT recipients and has been reported to account for between 40% and 60% of cases. 4,5 In SOT recipients, IA is the second most common IFD overall, but the leading IFD in lung transplant recipients. 6 Mortality from IA is substantial in both patient populations. In prospective, multicenter, observational studies, the overall 6-week mortality rate among HSCT recipients with IA in North America was 22% 5 and 1-year mortality rate in the United States (US) was 75%. 4 In a separate prospective, multicenter, observational study, the 1-year mortality rate among SOT

Clinical Pharmacokinetics and Drug‐Drug Interaction Potential for Coadministered SCY‐078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus

“…30 The results of this study show that coadministration of a single-dose of tacrolimus with SCY-078 at steady state resulted in a modest 1.4-fold increase in systemic exposure to tacrolimus (AUC 0-Ý ) and 1.7-and 1.5-fold increases in trough concentrations (C 12 and C 24 ) compared with administration of tacrolimus alone, consistent with SCY-078 being a weak inhibitor of CYP3A4 (AUC increased by ࣙ1.25fold but ࣘ2-fold). 21,22 C max and t max of tacrolimus were similar whether given alone or with SCY-078. These data indicate a lower risk for clinically meaningful effect of SCY-078 on tacrolimus exposure than seen with the azoles.…”

“…These data led to a recommendation for a 50% to 75% dose reduction and frequent monitoring of tacrolimus blood levels when coadministered with azoles. 21 In contrast, in vitro data support that at clinically relevant exposures SCY-078 will have no or weak effects on sensitive CYP3A4 substrates such as midazolam or tacrolimus (<2-fold increase in substrate exposure). 22 The primary objective of this study is to assess the effect of SCY-078 on tacrolimus.…”

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders

“…VCZ is indicated for prophylaxis and treatment of invasive fungal infection (IFI), primarily invasive aspergillosis . Patients with a declined immune system such as patients administered immunosuppressant agents and hematologic malignancy are at higher risk for developing a serious IFI such as invasive aspergillosis, disseminated candidiasis, or cryptococcal meningitis . Even though the incidence of IFI in this subgroup of patients is low, the mortality rate is very high (over 80% for invasive aspergillosis) without effective treatment .…”

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

“…PUR1900 steady state AUC 0‐24h was 106‐ and 400‐fold lower for the 35‐ and 10‐mg doses, respectively, than that achieved with the exposure observed with twice daily dosing of oral Sporanox solution (29 271 ng h/mL) in healthy subjects in a previous study . Itraconazole and hydroxy‐itraconazole are potent inhibitors of cytochrome p450 3A4 and contraindicated with a number of drugs and drug classes due to risks of significant drug–drug interactions and cardiovascular events . Further, the probability of AEs associated with oral itraconazole dosing increase with increasing plasma concentrations of itraconazole and therapeutic drug monitoring is important during treatment .…”

“…22 Itraconazole and hydroxyitraconazole are potent inhibitors of cytochrome p450 3A4 and contraindicated with a number of drugs and drug classes due to risks of significant drug-drug interactions and cardiovascular events. 23 Further, the probability of AEs associated with oral itraconazole dosing increase with increasing plasma concentrations of itraconazole and therapeutic drug monitoring is important during treatment. 11,24 PUR1900 may reduce the risks of AEs and improve the therapeutic window relative to oral itraconazole due to substantially reduced plasma exposure following inhalation.…”