A Bayesian approach for population pharmacokinetic modelling of sirolimus

Abstract

AimsTo explore a Bayesian approach for the pharmacokinetic analysis of sirolimus concentration data arising from therapeutic drug monitoring (poorly informative concentration-time point design), and to explore possible covariate relationships for sirolimus pharmacokinetics. MethodsSirolimus concentration-time data were available as part of routine clinical care from 25 kidney transplant recipients. Most samples were taken at or near the trough time point at steady state. The data were analyzed using a fully conditional Bayesian approach with PKBUGS (v 1.1)/WinBUGS (v 1.3). Features of the data included noncompliance and missing concentration measurements below the limit of sensitivity of the assay. Informative priors were used. ResultsA two-compartment model with proportional residual error provided the best fit to the data (consisting of 315 sirolimus concentration-time points). The typical value for the apparent clearance (CL/ F ) was 12.5 l h − 1 at the median age of 44 years. Apparent CL was found to be inversely related to age with a posterior probability of a clinically significant effect of 0.734. ConclusionsA population pharmacokinetic model was developed for sirolimus using a novel approach. Bayesian modelling with informative priors allowed interpretation of a significant covariate relationship, even using poorly informative data.

Population Pharmacokinetics of Sirolimus in Pediatric Patients With Neurofibromatosis Type 1

“…In adults and children, sirolimus clearance has been reported to be associated with patient age 18-20 . Dansirikul and colleagues reported sirolimus clearance was inversely related to age in 25 adult renal transplant patients 18 .…”

“…In adults and children, sirolimus clearance has been reported to be associated with patient age 18-20 . Dansirikul and colleagues reported sirolimus clearance was inversely related to age in 25 adult renal transplant patients 18 . Similarly, Schachter and colleagues reported the sirolimus half-life to be shorter in children compared to adult data (10-24 hours vs 49-70 hours, respectively) based on their analysis of 24 sirolimus pharmacokinetic profiles in 13 pediatric renal transplant patients 19 .…”

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 …”

“…There are several publications regarding the pharmacokinetics of sirolimus in transplant patients, although none have explicitly incorporated the nonlinear pharmacokinetic characteristics into a mixed‐effects population model 8 , 9 , 10 , 11 , 12 . Jiao et al .…”

Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients

“…Although an inverse relationship was found between SRL clearance and age in a population pharmacokinetic study of 25 kidney transplant recipients, patients aged N50 years in this study only made up 25% of the total sample size [80]. With the dramatic increase in the number of elderly transplant recipients in the last decade, more pharmacokinetic studies of mammalian target of rapamycin (mTOR) inhibitors with sufficient number of elderly transplant patients are needed, so as to better understand the role of age in drug variability.…”