Population Pharmacokinetics of Sirolimus in Adult Liver Transplant Recipients: Implications for Individualized Dosing

Sirolimus is an immunosuppressive medication commonly used after solid organ transplantation. Its use is characterized by a narrow therapeutic index and fluctuating pharmacokinetic exposure, making it essential to pinpoint the sources of this variability and to devise individualized treatment strategies. The goal of this work was to conduct a population pharmacokinetic (PK) evaluation of sirolimus in adult liver transplant recipients and to generate dosage recommendations tailored to patient-specific factors. For the analysis, a collection of 216 sirolimus concentration readings from whole blood was gathered from 103 adult subjects. A stepwise method was used to identify covariates affecting the PK profile of sirolimus. To propose dosing protocols for individuals presenting with varying covariate magnitudes, Monte Carlo simulations were undertaken. A one-compartment model with first-order elimination best represented the dataset. The apparent clearance of sirolimus was notably impacted by hematocrit (HCT). Based on Monte Carlo simulations, for subjects with a reduced HCT of 28%, protocols involving 1.5 mg once daily or a rotation between 1 mg once daily and 1.5 mg once daily were advisable. For subjects with a standard HCT level, the suggested protocols were 1 mg once daily, 2 mg every other day, or a rotation between 0.5 mg once daily and 1 mg once daily. Drawing on our population PK model of sirolimus in adult liver transplant recipients, which constitutes the most extensive sample to date, we propose that dosing protocols be customized to accommodate distinct HCT levels in these patients.