POPULATION PHARMACOKINETICS OF TENOFOVIR IN THAI HIV-INFECTED PATIENTS

Abstract

Background: Tenofovir has high interindividual variability. Genetic variation of drug transporters may contribute to high interindividual variability of tenofovir. Therefore, the aims of study were to develop population pharmacokinetic model and identify factors, both genetic and non-genetic factors, influencing pharmacokinetic parameters of tenofovir in order to provide initial information for dose optimization. Methods: This study is a retrospective descriptive study. A total of 342 Thai HIV-infected patients from clinical studies of The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) were included for the population pharmacokinetic model development using nonlinear mixed effects model (NONMEM) and 103 patients from Pharmacogenomics and Personalized Medicine, Ramathibodi Hospital database were used for model validation using Bayesian estimation. Results: Pharmacokinetics of tenofovir can be best described by a two-compartment model with first order absorption and elimination. The estimated glomerular filtration rate calculated by Cockcroft and Gault formula, concomitant use of lopinavir/ritonavir and ABCC4 3463A>G polymorphism were associated with apparent oral clearance (CL/F) of tenofovir. The concomitant use of lopinavir/ritonavir decreased CL/F of tenofovir by 25.1%. Patients carrying at least 1 variant allele of ABCC4 3463 A>G (genotype AG or GG) had tenofovir CL/F 10.5% higher than those with wild type (genotype AA). For model validation, the Bland-Altman plot showed no systematic bias. However, the mean prediction error of the final model was -0.00452 mg/l and it was significantly different from zero (p=0.029), indicating that the final model tended to underpredict the concentrations. Conclusions: Renal function, comedication and genetic variation had impact on the pharmacokinetics of tenofovir. These factors should be considered when tenofovir is prescribed to ensure efficacy and safety of the drug.