Population pharmacokinetics-pharmacogenetics of efavirenz and population pharmacokinetics of lopinavir/ritonavir in Thai HIV-infected patients

Abstract

Introduction: When dolutegravir (DTG) is not readily available, efavirenz (EFV) is one of the alternatives for the initial human immunodeficiency virus (HIV) type 1 treatment, according to the Thailand National Guidelines on HIV/AIDS Diagnosis, Treatment and Prevention 2020/2021. When EFV or other NNRTIs are unable to be used, lopinavir/ritonavir (LPV/r), the drug in the protease inhibitors (PIs), is a substitute medication for HIV therapy. The fixed dose of EFV is 600 mg once daily for Thai people living with HIV (PLWH) and HIV/tuberculosis (TB) co-infected patients receiving rifampin (RIF) as co-medication. In parallel, the fixed doses of LPV/r are 400/100 mg and 800/200 mg twice daily for Thai PLWH and PLWH receiving RIF, respectively. However, unanticipated efficacy and toxicity were commonly observed due to high inter-individual variabilities in EFV and LPV/r concentrations. These variabilities might be explained by several factors and could be used to provide dose individualization. Nevertheless, the model-based individualized doses of EFV and LPV/r in the Thai population have not been suggested. Thus, this study aimed to develop population pharmacokinetic models of EFV and LPV/r and investigate the factors that impact EFV and LPV/r pharmacokinetics. Moreover, the developed EFV and LPV/r models were used for dose optimization for Thai PLWH with and without RIF. Methods: The steady-state plasma EFV concentrations were measured at 12 h post-dose from 360 Thai PLWH, and the trough steady-state plasma LPV and ritonavir (RTV) concentrations were obtained from 206 Thai PLWH. Additionally, intensive LPV and RTV data collected at pre-dose, 1, 2, 4, 6, 8, 10, and 12 h post-dose from 32 Thai PLWH were included in the analysis of LPV/r. The population pharmacokinetic analyses of EFV and LPV/r were performed using a nonlinear mixed-effect modeling approach. For LPV and RTV interaction model, the impact of RTV concentrations on LPV pharmacokinetics was explored. The simulations were conducted to investigate different dose reduction regimens and determine the optimal dosages of EFV and LPV/r. The percentages of in silico patients having simulated plasma concentrations within the therapeutic range were compared across the dosage regimens. Results: A one-compartment model with first-order absorption and elimination was used to describe EFV pharmacokinetics. The CYP2B6 516G>T polymorphism, weight, and RIF use were significant covariates affecting the apparent oral clearance (CL/F) of EFV. The CL/F of EFV was 11.9, 8.0, and 2.8 L/h in PLWH weighing 57 kg carrying CYP2B6 516GG, 516GT, and 516TT genotype, respectively. The use of RIF increased EFV CL/F by 28%. The results of simulations suggested EFV doses of 400, 300, and 100 mg once daily for Thai PLWH and 800, 600, and 200 mg once daily for Thai PLWH receiving RIF carrying CYP2B6 516GG, 516GT, and 516TT, respectively. For the LPV/r, a one-compartment model with transit-compartmental absorption best described the pharmacokinetics of LPV and RTV. The use of RIF was a significant covariate affecting the CL/F of LPV and RTV. The impact of RTV plasma concentration on the CL/F of LPV was best described by a maximum inhibition model. The IC50 was estimated to be 0.207 mg/L when Imax was fixed to 1. The CL/F of LPV in the absence and presence of RTV was 15.4 L/h and 4.69 L/h, respectively. The simulation results showed that the reduced LPV/r doses of 300/75 mg or 200/150 mg twice daily could be used for PLWH to maintain LPV plasma concentrations within the therapeutic range. Moreover, the reduced LPV/r dose of 600/150 mg twice daily could be used for PLWH with active TB receiving RIF who do not tolerate the standard dose of LPV/r. Conclusions: This is the first population pharmacokinetics of EFV and LPV/r in Thai PLWH with and without active tuberculosis. The simulations investigating the optimal doses of EFV in Thai PLWH provided the rationale for individualizing dosage regimens of EFV based on CYP2B6 516G>T polymorphism. These developed models could help optimizing EFV and LPV/r dosage regimens for Thai PLWH to ensure efficacy and reduced toxicities.