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

UGT1A1, NR1I2

Dolutegravir apparent clearance reduced by the combination of a UGT1A1 poor metabolizer phenotype and the NR1I2 63396 TT genotype, interacting with low body weight

Dolutegravir, a first-line HIV therapy for Thai people living with HIV, shows substantial pharmacokinetic variability of both genetic and non-genetic origin, which may contribute to the neuropsychiatric adverse events seen at the standard 50 mg once-daily dose. A population pharmacokinetic model was built from 1,122 plasma concentrations in 221 Thai people living with HIV, using a one-compartment model with first-order absorption, lag time and first-order elimination. Body weight below 61 kg and a multigenic interaction emerged as significant covariates of apparent clearance: individuals carrying both the UGT1A1 poor metabolizer phenotype and the NR1I2 63396 TT genotype had a 25.1% reduction in clearance. Monte Carlo simulations indicated that the standard dose met efficacy targets in over 95% of the population but exceeded the safety threshold in 30.46-85.68%, whereas a reduced 25 mg once-daily dose maintained efficacy target attainment above 80% while bringing the proportion above the safety threshold below 20% in most subgroups.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 25.1% clearance reduction driven by the UGT1A1/NR1I2 combination fits dolutegravir glucuronidation and the regulatory role of NR1I2, but it remains a model covariate rather than a clinical endpoint. No direct link between genotype and neuropsychiatric events is established here: the 25 mg dose comes from simulations, not from a trial. Read it as a de-escalation hypothesis to be tested in low-weight patients carrying these genotypes, not as a dosing recommendation.

Analysis by Dr Thibaut Benquey