Tacrolimus dose modification in patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation

Abstract

Introduction Isavuconazole is increasingly being used for antifungal prophylaxis during stem cell transplantation. Isavuconazole is a moderate inhibitor of Cytochrome P4503A4, and tacrolimus levels are anticipated to be elevated when given concomitantly with isavuconazole. We developed and validated a dose-modified tacrolimus regimen to better achieve and maintain target tacrolimus levels. Methods: Allogeneic stem cell transplantation recipients who received concomitant tacrolimus and isavuconazole from September 2017 to September 2018 were included. Tacrolimus was adjusted to achieve a target range 8–12 ng/ml. Intravenous tacrolimus was first initiated at 0.02 mg/kg/day on day 1, and transitioned to oral therapy using a 2:1 conversion ratio ( n = 48). Clinical observations showed high interpatient variability. The intravenous dose was then reduced to 0.017 mg/kg/day, and oral:intravenous conversion changed to 3.1:1 ( n = 24). Results Interpatient variability was high (lower in the 0.017 mg/kg/day group; P < 0.0217). Patients in the 0.017 mg/kg/day group required fewer dose changes ( P < 0.023) and had fewer levels >15 ng/ml ( P < 0.021). Median tacrolimus dose declined over time; 0.016, 0.012 and 0.011 on days 1, 7 and 10 for patients receiving 0.02 mg/kg/day and 0.017, 0.014 and 0.013 in the 0.017 mg/kg group. Day 10 tacrolimus accumulation factor was 1.42 Rac(Cmax) in the 0.02 mg/kg/day cohort compared to 1.23 Rac(Cmax) in the 0.017 mg/kg/day cohort ( P < 0.015). When transitioned to oral therapy, a oral:intravenous conversion ratio >3.1:1 was shown to improve chances for achieving target levels ( P > 0.0744). Conclusion We recommend initiating intravenous tacrolimus dose at 0.017 mg/kg/day and using a 3.1:1 oral:intravenous conversion to reduce interpatient variability, drug accumulation and the number of suboptimal tacrolimus levels. Tacrolimus requires frequent drug level monitoring.

Recommendations on the use of azole antifungals in hematology-oncology patients

“…With isavuconazole, it does not appear necessary to adjust the tacrolimus dose at the start of treatment [ 189 ], although it has been recommended that an initial tacrolimus dose of 0.017 mg/kg be administered instead of the usual 0.02 mg/kg [ 190 ]. In the case of liver transplantation, a 30% dose reduction was recommended [ 191 ].…”

Antifungal Drugs TDM: Trends and Update

“…The following are important issues to be borne in mind:The role of steroids as targets 220 but also as inhibitors in cases of acute high-dose treatment and as moderate inducers during chronic low-dose treatment (VRZ), 221–224 The role of the administration route for victim drugs and possible differences in DDI magnitude after switches between IV and oral formulations 225–227 (tacrolimus/ISZ; VRZ). The difference in dosing due to oral bioavailability must be counterbalanced by the magnitude of inhibition 228 (cyclosporine/FCZ, VRZ),The documentation of azole perpetrator exposure, even in the absence of a direct correlation with changes in victim drug concentration, may facilitate DDI management, particularly in cases of long half-life and/or high PK variability,Particular caution is required when withdrawing interacting treatments, 229 including induction, or persistent inhibition in cases of switches between azoles, 230 PK DDI is a major concern for azoles, but the risk of PD DDI must be considered for other hepatotoxic drugs (with ITZ, VRZ), other neurotoxic drugs 231 (such as vincristine and VRZ), and cardiac QT modifiers (risk of prolongation with ITZ, VRZ, PSZ; or shortening with ISZ).…”

“…The role of the administration route for victim drugs and possible differences in DDI magnitude after switches between IV and oral formulations 225–227 (tacrolimus/ISZ; VRZ). The difference in dosing due to oral bioavailability must be counterbalanced by the magnitude of inhibition 228 (cyclosporine/FCZ, VRZ),…”