Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults

Groll, Andreas H.; Desai, Amit; Han, David; Howieson, Corrie; Kato, Kota; Akhtar, Shahzad; Kowalski, Donna; Lademacher, Christopher; Lewis, William; Pearlman, Helene; Mandarino, Debra; Yamazaki, Takao; Townsend, Robert

doi:10.1002/cpdd.284

Cited by 103 publications

(92 citation statements)

References 11 publications

(32 reference statements)

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“…Groll and colleagues demonstrated a 2.25-fold increase in tacrolimus concentrations when tacrolimus was administered 2 days after isavuconazole loading dose in healthy volunteers (10). Although both Groll et al and our study demonstrated that a drug-drug interaction exists between isavuconazole and tacrolimus (presumably through the inhibition of CYP3A4 by isavuconazole), the degree of drug interaction differed.…”

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confidence: 52%

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

Rivosecchi

Clancy

Shields

et al. 2017

Antimicrob Agents Chemother

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We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.KEYWORDS isavuconazole, drug interactions, pharmacokinetics, tacrolimus, zygomycetes A ntifungal prophylaxis is commonly administered following solid-organ transplant (SOT) to prevent invasive fungal infections (1). Tacrolimus, a primary immunosuppressive agent in SOT, is a substrate of cytochrome P450 (CYP) 3A4. The triazole antifungals are CYP3A4 inhibitors that have varied effects on tacrolimus metabolism (2, 3). The manufacturers of voriconazole and posaconazole recommend an empirical reduction of one-third in the daily tacrolimus dose; however, in clinical practice the required reduction is often substantially greater (4, 5). Isavuconazole acts as both a substrate and inhibitor of CYP3A4 (6-8). Currently, there are no definitive dosing recommendations for tacrolimus in patients receiving isavuconazole. Following a cluster of mucormycosis cases among SOT recipients at the University of Pittsburgh Medical Center (UPMC), universal isavuconazole prophylaxis was instituted (Table 1). The objective of this study was to evaluate the effects of isavuconazole on whole-blood trough tacrolimus concentrations in various SOT populations.We performed a retrospective study of consecutive patients who underwent SOT at UPMC between 15 September 2015 and 10 February 2016 and who were initiated on isavuconazole prophylaxis for Ն21 days. Patients were required to have received tacrolimus, have had follow-up for Ն40 days after isavuconazole was stopped, and have had whole blood tacrolimus concentrations measured during and following isavuconazole prophylaxis. Patients were excluded if they were on tacrolimus or other azoles at the time of transplantation or if they required renal replacement therapy beyond the first 5 days after transplantation.A total of 55 SOT recipients were included (Table 2). Tacrolimus levels were obtained during (n ϭ 1,098) or following (n ϭ 3,080) isavuconazole prophylaxis. Tacrolimus

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confidence: 52%

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

Rivosecchi

Clancy

Shields

et al. 2017

Antimicrob Agents Chemother

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“…Studies and prescribing information indicate that concurrent administration of voriconazole increases the exposure concentrations of these immunosuppressant drugs modestly or markedly (Table ). In seven kidney transplant recipients who completed a randomized, double‐blind, placebo‐controlled, crossover study, 7.5 days of oral voriconazole administration (200 mg BID) increased the AUC for the dosing interval (AUC 0‐τ ) of oral cyclosporine (150‐375 mg/day) by 1.7‐fold .…”

Section: Effects Of Triazole Antifungals On the Pharmacokinetics Of Cmentioning

confidence: 99%

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

Groll

Townsend

Desai

et al. 2017

Transplant Infectious Dis

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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

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“…Lopinavir and ritonavir are substrates of CYP3A,7 and the combined drug is a strong inhibitor of these isoenzymes 8, 9, 10. Lopinavir and ritonavir are also inhibitors of P‐gp11, 12 as well as organic anion‐transporting polypeptides 1B1 (OATP1B1) and 1B3 (OATP1B3) 13.…”

mentioning

confidence: 99%

Pharmacokinetic Interaction Between Isavuconazole and a Fixed‐Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects

Yamazaki

Desai

Han

et al. 2016

Clinical Pharm in Drug Dev

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This phase 1, open‐label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water‐soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone. Mean area under the concentration‐time curve (AUC) following the last dose (AUCτ) and Cmax of isavuconazole increased by 113% and 96% in part 1 and by 96% and 74% in part 2 in the presence vs absence of lopinavir/ritonavir, respectively. Mean AUCτ and Cmax of lopinavir were 27% and 23% lower, and mean AUCτ and Cmax of ritonavir were 31% and 33% lower in the presence vs absence of isavuconazole, respectively. Mild to moderate gastrointestinal disorders were the most common adverse events experienced. These findings indicate that coadministration of lopinavir/ritonavir with isavuconazole can decrease the exposure of lopinavir/ritonavir and increase the exposure of isavuconazole. Patients should be monitored for reduced antiviral efficacy if these agents are coadministered.

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Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults

Cited by 103 publications

References 11 publications

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

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

Pharmacokinetic Interaction Between Isavuconazole and a Fixed‐Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects

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