Population pharmacokinetics of sirolimus inde novoChinese adult renal transplant patients

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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection.• Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African‐American recipients.WHAT THIS STUDY ADDS?• The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time.• New drug–drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance.AIMS: This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability inde novoChinese adult renal transplant patients.METHODS: Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12‐month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight‐hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using thenonmemprogram. A one‐compartment model with first‐order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporinC0as well as other commonly used co‐medications were explored.RESULTS: The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h−1(23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/Fdecreased significantly with silymarin or glycyrrhizin co‐therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporinC0. Moreover, CL/Fincreased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates fromnonmem.CONCLUSIONS: These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.

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