Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

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. AIMSThis study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODSData 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 (C 0) from 112 patients were used to develop a population pharmacokinetic model using the NONMEM program. 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, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTSThe 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/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from NONMEM. CONCLUSIONSThese results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.

Steady‐state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients

“…Although there were no formal statistical comparisons performed, the observed mean oral clearance of sirolimus in this study for patients receiving CsA appears to be consistent with values reported from studies mainly in white and black patients using NCA (133–143 mL/h/kg) . It is also in agreement with the estimates from Chinese renal transplant patients using a population approach (168 mL/h/kg [10.1 L/h]) for sirolimus. It should be noted that when the relevant mean C trough value in patients taking concomitant CsA was normalized to a 2‐mg dose (7.0 ± 3.6 ng/mL), it appeared to be consistent with the mean trough concentration values (8.59 ± 4.01 and 8.06 ± 4.03 ng/mL) observed in two pivotal phase 3 trials in renal transplant patients, taking into consideration that different bioanalytical methods were employed for quantification of sirolimus .…”

“…Despite differences in the sirolimus dosing regimens, in patient demographic characteristics and disease states, and in the combination therapies between this study and those used in previous investigations, the pharmacokinetic parameters are generally consistent with those reported in studies in Western populations and are consistent with those suggested from a previous population pharmacokinetic analysis in Chinese renal transplant recipients …”

Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

“…Sirolimus has low bioavailability (14% on average) and a long terminal elimination half‐life of ~62 h 7 . Studies in transplant patients have demonstrated marked interindividual pharmacokinetic variability, resulting in the widespread use of therapeutic drug monitoring based on whole blood concentrations 8 , 9 , 10 , 11 , 12 , 13 …”

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure–Response Relationships in Renal Transplant Patients

“…18-21 Differences in apparent oral clearance between our population and others may be related to variability in cyclosporine use and exposure, differences in extent of CYP3A4 and CYP3A5 expression, other disease states (e.g., liver disease and cancer), and other drug interactions. 18,19,22,23 Unlike other studies that have developed population PK models, we identified age as an important covariate for apparent clearance. This finding may reflect the relatively more advanced median age of patients in our study (59, range 29 to 72 compared to 48.6, range 20 to 69), and potential influences of age on CYP3A4 activity.…”