Impact of Body Weight and Combined UGT1A1 and NR1I2 Polymorphisms on Dolutegravir Pharmacokinetics Among Thai People Living with HIV: A Population Pharmacokinetic Analysis

Background/Objectives: Despite its role as a first-line therapy for Thai people living with HIV (PLWH), dolutegravir (DTG) exhibits significant pharmacokinetic (PK) variability influenced by both genetic and non-genetic factors. This variability may contribute to an increased incidence of neuropsychiatric adverse events (NP-AEs) at the standard 50 mg once daily (OD) dose. Methods: To evaluate the impact of relevant covariates, a population PK model of DTG was developed using 1122 DTG plasma concentrations from 221 Thai PLWH. Monte Carlo simulations were performed to evaluate the probability of target attainment for pre-defined efficacy and safety thresholds across different dosage regimens. Results: Data were analyzed using a one-compartment model with first-order absorption incorporating lag-time, and first-order elimination. Body weight (<61 kg) and a multigenic interaction were identified as significant covariates impacting DTG apparent clearance (CL/F). Specifically, individuals carrying both the UGT1A1 poor metabolizer phenotype and the NR1I2 63396 TT genotype resulted in a 25.1% reduction in DTG CL/F. Simulation results indicated that the standard dose achieved efficacy targets in > 95% of the population but resulted in a substantial proportion (30.46–85.68%) exceeding the safety threshold. In contrast, a reduced dose of 25 mg OD maintained high efficacy target attainment (>80%) while decreasing the proportion exceeding the safety threshold to <20% in most subgroups. Conclusions: These findings suggest that a reduced DTG dose may be a suitable alternative for Thai PLWH to mitigate the risk of NP-AEs, particularly among individuals with low body weight carrying the combined UGT1A1 and NR1I2 variants.