Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring

Kim, T.; Jancel, Timothy; Kumar, Parag; Freeman, Alexandra F.

doi:10.1111/jcpt.12308

Cited by 29 publications

(30 citation statements)

References 2 publications

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“…Moreover, Groll included young (mean age, 35 years), healthy volunteers who were on no other drugs, whereas our patients were older (mean age, 60 years), critically ill, and within a month of transplant. Our results, combined with the considerable interpatient variability in the magnitude of the drug interaction (11), suggest that tacrolimus should not be administered using uniform dose reductions among patients receiving isavuconazole, but rather guided by therapeutic drug monitoring. This conclusion differs from the standard dose reductions that are recommended when initiating or discontinuing voriconazole or posaconazole (4,5).…”

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confidence: 87%

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: 87%

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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“…One study in healthy adults reported increases in tacrolimus and sirolimus exposure when combined with isavuconazole . One study and one case report in solid organ transplant patients also indicated increases in tacrolimus exposure when combined with isavuconazole . However, one case report in an alloHSCT patient indicated that no empiric dose reduction in tacrolimus was needed when combined with isavaconazole …”

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confidence: 99%

Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: A drug‐drug interaction study

Kieu

Jhangiani

Dadwal

et al. 2018

Transplant Infectious Dis

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Introduction Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3‐fold and 1.8‐fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3‐fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. Methods A retrospective, single‐center, single‐arm study in adult alloHSCT patients who received at least 10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to 4 weeks. Results Twenty‐two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42‐fold for tacrolimus during week 1 (P = 0.002) and up to 1.56‐fold for sirolimus during week 2 (P = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline. Conclusion In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole.

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“…However, we increased the interval between TAC doses. The level of interaction between isavuconazole and immunosuppressive agents did not appear to be as high as has been reported for other triazole antifungal agents . In a recent report, the interaction between isavuconazole and TAC differed by the transplanted organ, with considerable interpatient variability .…”

Section: Discussionmentioning

confidence: 61%

Successful treatment with isavuconazole of subcutaneous phaeohyphomycosis in a kidney transplant recipient

Gasperina

Lombardi

Rovelli

et al. 2019

Transplant Infectious Dis

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Phaeohyphomycosis is a diverse group of uncommon mycotic infections caused bydematiaceous fungi which appears to be increasing in incidence, particularly in transplant recipients. Alternaria is the most frequent isolated genus. Subcutaneous, pulmonary and disseminated disease are the most common sites of Alternaria infection in solid organ transplant recipients. We report the first case, to our knowledge, of a kidney transplant recipient with Alternaria alternata subcutaneous infection who was successfully treated with isavuconazole.

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Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring

Cited by 29 publications

References 2 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

Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: A drug‐drug interaction study

Successful treatment with isavuconazole of subcutaneous phaeohyphomycosis in a kidney transplant recipient

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