Population Pharmacokinetic-Pharmacogenetic (PopPK-PGx) Model of Efavirenz in HIV-1-Infected Patients

Background and objectives Efavirenz (EFV) exhibits substantial inter-patient pharmacokinetics (PK) variability. Polymorphisms in genes involved in EFV metabolism have been associated with EFV exposure, but they have not been fully implemented to inform dosing in treatment guidelines. This work aimed to develop a population pharmacokinetic-pharmacogenetic (PopPK-PGx) model of EFV in human immunodeficiency virus type 1 (HIV-1)-positive patients, and to simultaneously explore the influence of CYP2B6 (516G>T and c.485-18C>T) and NR1I3 polymorphisms, as well as patient characteristics on EFV PK parameters. Additionally, this study aimed to simulate the combined effects of genetic polymorphisms and nonadherence patterns on EFV plasma concentrations. Methodology Data from 89 patients receiving 600 mg EFV once daily were analyzed using NONMEM (v7.3) (ICON Development Solutions: Ellicott City, MD). For the structural model, considering a sparse sampling design, a one-compartment model was chosen to describe the distribution of EFV concentrations, with the oral volume of distribution (V/F) and constant rate of absorption (kA) fixed to literature-reported values. Bootstrapping and normalized prediction distribution errors (NPDE) were used for internal validation of the final model. Simulation of concentration-time profiles was conducted using the final PopPK-PGx model, following the recommended dosing regimen for typical individuals, to assess the probability of achieving target concentrations (1000-4000 ng/mL) under different PGx backgrounds and the effect of various nonadherence scenarios. Result Typical oral clearance (CL/F) was 13.9 L/h with 13.1% interindividual variability (IIV). CYP2B6 516G>T, and CYP2B6 c.485-18C>T were associated with EFV CL/F. On average, EFV CL/F was 36.4% lower in heterozygote patients for CYP2B6 516G>T. Moreover, on average, there is a 26.8% decrease in CL/F in patients with the TT genotype of CYP2B6 c.485-18C>T. The NPDE distribution plots confirmed that the model accurately predicted EFV concentrations. For individuals carrying either the CYP2B6 516G>T or CYP2B6 c.485-18C>T polymorphisms, missing two consecutive standard doses of 600 mg/day was estimated to be sufficient to drive EFV concentrations out of the therapeutic range, while for those not carrying any CYP2B6 polymorphisms, one missed dose was estimated to result in EFV concentrations falling below the therapeutic range. Conclusion These findings support the need for genotype-adherence-guided EFV dose adjustments to achieve optimal therapeutic levels. The CYP2B6 516G>T and c.485-18C>T variants were found to significantly reduce efavirenz rate of elimination, resulting in prolonged drug exposure. This insight could inform personalized strategies to maintain therapeutic concentrations in patients with varying adherence patterns.