Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.
- 1Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Abstract
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/m2 at 1000-3000 mg once daily compared to a DTG-free reference model. Fifteen women contributed evaluable profiles (mean BMI 45.6 kg/m2). 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.
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BibTeX
@article{benecke2026mechanistic,
title = {{Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.}},
author = {Rohan M Benecke and Veshni Pillay-Fuentes Lorente and Eric Decloedt and Roland van Rensburg},
journal = {Clinical pharmacology and therapeutics},
year = {2026},
month = nov,
doi = {10.1002/cpt.70565},
url = {https://europepmc.org/article/MED/42998045},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.
AU - Rohan M Benecke
AU - Veshni Pillay-Fuentes Lorente
AU - Eric Decloedt
AU - Roland van Rensburg
PY - 2026
DA - 2026/11/07
JO - Clinical pharmacology and therapeutics
DO - 10.1002/cpt.70565
UR - https://europepmc.org/article/MED/42998045
AB - 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/m2 at 1000-3000 mg once daily compared to a DTG-free reference model. Fifteen women contributed evaluable profiles (mean BMI 45.6 kg/m2). 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.
SN - 0009-9236
SN - 1532-6535
ER -