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

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Antifungal 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 ≥21 days. Patients were required to have received tacrolimus, have had follow-up for ≥40 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 = 1,098) or following (n = 3,080) isavuconazole prophylaxis. Tacrolimus concentration/dose (C/D) ratios were normalized for body weight and calculated as [tacrolimus trough level/(total tacrolimus daily dose/actual body weight)] (9). While on isavuconazole, the median tacrolimus C/D was highest on day 4, reflecting the effects of isavuconazole loading doses (Fig. 1). C/D stabilized by day 8. The median tacrolimus C/D was higher among liver recipients than among other organ recipients (P = 0.002). C/D distributions showed wide variations within each of the transplant groups (Table 2). After discontinuation of isavuconazole, median tacrolimus C/D gradually decreased, stabilizing at approximately 28 days (Fig. 1).

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FIG 1

Tacrolimus concentration/dose (C/D) ratios of solid-organ transplant patients. Individual diamonds represent median tacrolimus C/D ratios for all patients at indicated times on isavuconazole prophylaxis (A) and off isavuconazole prophylaxis (stopped on day 0) (B). In panel A, tacrolimus C/D ratios were evaluated after the first full day of isavuconazole and tacrolimus therapy (i.e., postoperative day 2).

In comparing tacrolimus C/D while on and off isavuconazole, ratios were considered at days 8 to 21 and days 28 to 60, respectively; these time points were selected based on our data described above (Fig. 1) and to account for the prolonged half-life of isavuconazole (∼80 to 100 h) (6). Overall, the median tacrolimus C/D was higher on isavuconazole than off (125 and 120 ng/ml per mg/kg, respectively; P = 0.037). On a per-patient basis, tacrolimus C/D was reduced by a mean of 13% after isavuconazole discontinuation. Liver transplant recipients experienced the largest per-patient tacrolimus C/D reduction (36% versus 8% in heart, 3% in lung, and 1% in kidney recipients; P = 0.047) (Fig. 2). Differences in tacrolimus C/D were not evident between SOT groups off isavuconazole (P = 0.59).

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FIG 2

Tacrolimus C/D (median ± interquartile range) on and off isavuconazole stratified by type of organ transplant. (A) Tacrolimus C/D on isavuconazole. Tacrolimus C/D was higher among liver transplant patients (median, 191.8) than kidney (median, 123.7; P = 0.046), heart (median, 104.7; P = 0.02), and lung transplant patients (median, 106.3; P = 0.01). (B) Tacrolimus C/D off isavuconazole. There was no difference in tacrolimus C/D among types of organ transplant patients (P = 0.59).

The median daily tacrolimus doses on and off isavuconazole were 6 and 8 mg, respectively (Table 2). The corresponding median tacrolimus levels were 11 and 9 μg/ml, respectively. To estimate the potential tacrolimus dose for individual patients after discontinuing isavuconazole, we calculated the estimated tacrolimus daily dose off isavuconazole as (daily tacrolimus dose while on isavuconazole/[tacrolimus level on isavuconazole · tacrolimus level off isavuconazole]). The calculated value for all patients was 6.1 mg. The ratio of the median actual tacrolimus dose taken by the patients off isavuconazole to the calculated estimated tacrolimus dose was 1.3. In other words, tacrolimus dose was increased by a median of 1.3-fold after isavuconazole was discontinued.

Age, race, sex, use of proton pump inhibitor, and liver transplantation status were evaluated in univariate analyses to determine associations with tacrolimus C/D. Liver transplant was the only factor that was significantly associated with tacrolimus C/D among patients receiving isavuconazole (P = 0.001). This association was no longer present after isavuconazole was discontinued (linear regression P = 0.68). We used Model for End-Stage Liver Disease (MELD) scores to assess the degree of liver dysfunction among liver transplant patients, and defined liver dysfunction as a MELD score >10. The MELD scores for liver transplant patients while on and off isavuconazole were 11 and 7, respectively (P = 0.0007). Fifty-six percent (10/18) and 17% (3/18) of liver transplant recipients had MELD scores >10 while on and off isavuconazole, respectively (P = 0.035). Results did not differ if C/D ratios were not normalized by weight.

To our knowledge, this is the first study that characterizes the interaction between isavuconazole and tacrolimus among SOT recipients. We used a population-based approach to evaluate the impact of isavuconazole on tacrolimus concentrations, which was feasible because of the large number of tacrolimus blood level measurements. Our results support three important conclusions. First, isavuconazole was associated with small but significant increases in tacrolimus levels among SOT recipients. Second, there was marked interpatient variability in tacrolimus levels. Finally, the interaction between isavuconazole and tacrolimus was more prominent among liver transplant patients than among other SOT recipients.

Overall, the per-patient tacrolimus C/D was reduced by a median of 13%, and the daily median tacrolimus dose to maintain specific tacrolimus levels was increased by 1.3-fold after isavuconazole was discontinued. 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. Notably, our analysis was performed with isavuconazole at steady state, in contrast to the loading phase used in the Groll study; studying the change in tacrolimus C/D while isavuconazole concentrations were at steady state provided a more accurate depiction of the magnitude of the drug-drug interaction. 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).

Our finding that the interaction between isavuconazole and tacrolimus differed by transplanted organ was novel. Indeed, the 13% decrease in tacrolimus C/D among our entire cohort following discontinuation of isavuconazole was driven largely by a 36% decrease among liver transplant patients; no other organ had a significant difference in tacrolimus C/D after isavuconazole was stopped. If liver transplant patients are removed from the cohort, the per-patient decrease in tacrolimus C/D was only 3%. MELD scores were higher within the first 4 weeks of liver transplantation (while patients were on isavuconazole prophylaxis) than thereafter (P = 0.0007), suggesting that abnormal liver function may have accounted for the association with tacrolimus C/D. Indeed, metabolism of isavuconazole and tacrolimus through the CYP3A4 pathway, which is known to exhibit both inter- and intrapatient variability after liver transplantation, was likely impaired during the time the patients were receiving both agents (12). Isavuconazole clearance is decreased in patients with moderate hepatic dysfunction, leading to a near doubling of half-life after a single dose (13). Desai and colleagues demonstrated a doubling of mean isavuconazole trough levels in patients with mild or moderate hepatic dysfunction (14). Of note, the difference in tacrolimus C/D between organs was no longer apparent 8 weeks after liver transplant, which may be attributable to recovery of hepatic function in the liver transplant patients. In the future, studies of isavuconazole pharmacokinetics (PK) following liver transplantation and other SOT are needed.

Isavuconazole is characterized by a large volume of distribution and prolonged half-life after multiple administrations (15, 16). In a dose-finding PK study, Schmitt-Hoffmann and colleagues noted an ∼4- to 5-fold accumulation factor between the first and final (day 14 or 21) day of isavuconazole administration, and steady-state volume of distribution of 308 to 542 liters (17). Based on a systemic clearance of 2.4 to 4.1 liters/hour in healthy volunteers, effects of isavuconazole would be expected to last for 75 to 226 h after discontinuation (17). Our SOT patients had persistently elevated tacrolimus C/D ratios >600 h after stopping isavuconazole (Fig. 1). The differences between our data and those of Schmitt-Hoffmann could be due to the longer course of isavuconazole in this study, with all patients receiving the drug for ≥1 month.

We acknowledge that our results may not be generalizable to patient populations other than SOT recipients, or to SOT recipients at other centers. Since isavuconazole levels were not evaluated, we were unable to determine if differences in isavuconazole concentrations may have been responsible for variations in tacrolimus C/D.

In conclusion, the interaction between isavuconazole and tacrolimus is most significant following liver transplantation, and relatively modest following other SOT. However, the impact of isavuconazole on tacrolimus levels varies significantly between individuals undergoing each type of transplant. In our program, we currently recommend against standardized tacrolimus dose reductions. Rather, we advocate close tacrolimus therapeutic drug monitoring (TDM) until levels are stable, at such time that isavuconazole levels are likely to have reached steady state (∼7 days). Programs should devise their own protocols for tacrolimus TDM upon initiation of isavuconazole, based on types of organ transplant and local experience. A complete PK analysis, including isavuconazole levels, is warranted to further define drug interactions.