Mechanistic Population Pharmacokinetic Modeling of Extended‐Release Metformin in Obese South African Women Living with HIV on Dolutegravir

Regulatory limits on metformin co‐administered with dolutegravir (DTG) derive from healthy‐volunteer studies in which DTG increased metformin exposure by 79% through organic cation transporter 2 inhibition, prompting a 1,000 mg/day metformin dose restriction. Whether this applies to women with HIV and severe obesity, a clinically important and understudied population for metformin‐DTG coadministration, is unknown. In a secondary analysis of a reported cohort, we developed a population pharmacokinetic model of extended‐release (XR) metformin with a zero‐order‐release, first‐order‐absorption structure scaled by lean body mass (LBM). Estimated glomerular filtration rate and DTG exposure were evaluated as clearance covariates, including DTG as a time‐varying competitive inhibitor. We simulated steady‐state exposures across body mass index (BMI) 30–60 kg/m 2 at 1000–3000 mg once daily compared to a DTG‐free reference model. Fifteen women contributed evaluable profiles (mean BMI 45.6 kg/m 2 ). Apparent clearance was 70.2 L/h, approximately 40% higher than reported non‐obese values, and DTG exposure was approximately 54% lower than in volunteer studies. LBM dominated clearance and volume, while no DTG exposure‐dependent effect on metformin clearance was identifiable within the observed low DTG exposure range. Simulated exposures rose near‐proportionally with dose and minimally with BMI; the proportion exceeding the lactic acidosis‐associated maximum concentration of 5 mg/L was 4.4% at 2000 mg/day, 16.9% at 2500 mg/day and 37.9% at 3000 mg/day, whereas none exceeded the lactic acidosis‐associated average steady‐state concentration of 4 mg/L. Although an interaction at higher DTG exposures cannot be excluded, the low exposures observed suggest the 1,000 mg/day restriction may underdose this obese population, supporting investigation of doses up to 2000 mg/day as the maximum authorized daily dose for metformin XR.