Population pharmacokinetics of nevirapine in HIV-infected patients

Abstract

Background Nevirapine plasma concentration has been shown to be associated with virological response, treatment failure and adverse drug reactions. Nevirapine has a high interindividual variability, therefore identifying sources of the variability of nevirapine pharmacokinetics is important for dose optimization. Objectives To develop a population pharmacokinetic model of nevirapine, to determine population mean pharmacokinetic parameters, and to identify factors influencing the pharmacokinetic parameters of nevirapine in HIV-infected patients. Methods A retrospective descriptive study in 236 patients, data were extractedfrom clinical studies from The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) and Bamrasnaradura Infectious Disease Institute. The model was developed by a nonlinear mixed-effects modeling approach using NONMEM®. Model validation was performed using Bayesian estimation. Results A one-compartment model with first-order absorption and elimination found to be the best model for describing nevirapine pharmacokinetics. Age more than 40 years and aspartate aminotransferase (AST) level more than 60 U/L decreased nevirapine apparent oral clearance (CL/F) by 18% and 16%, respectively. The concomitant use of rifampicin increased nevirapine CL/F by 22%. The results from model validation showed that the mean prediction error of the final model was -0.10 mg/L and was not significantly different from zero (p=0.49). The Bland-Altman plot showed no systematic bias. Conclusions The nevirapine CL/F in this population was slightly lower than previously reported in other populations. The patient characteristics which influence nevirapine CL/F were age as categorical variable (≤40 years, >40 years), AST level as categorical variable (≤60 U/L, >60 U/L) and rifampicin use. The model obtained from this study can be used for nevirapine dosage optimization for individual patient.