{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rohan M Benecke",
      "orcid": "0000-0002-8854-0380"
    },
    {
      "affs": [
        0
      ],
      "name": "Veshni Pillay-Fuentes Lorente",
      "orcid": "0000-0001-5365-0320"
    },
    {
      "affs": [
        0
      ],
      "name": "Eric Decloedt",
      "orcid": "0000-0003-1815-5150"
    },
    {
      "affs": [
        0
      ],
      "name": "Roland van Rensburg",
      "orcid": "0000-0002-6464-4257"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1cj10qhrs9vrg.bib",
  "cited_by": 0,
  "doi": "10.1002/cpt.70565",
  "fulltext_url": "https://europepmc.org/articles/PMC13744162",
  "id": "1cj10qhrs9vrg",
  "issns": [
    "0009-9236",
    "1532-6535"
  ],
  "landing_url": "https://europepmc.org/article/MED/42998045",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "3004|Pharmacogenetics and Drug Metabolism"
    ]
  ],
  "openalex": "W7225456932",
  "pdf_url": "https://europepmc.org/articles/PMC13744162?pdf=render",
  "pmcid": "PMC13744162",
  "pmid": "42998045",
  "published": "2026-11-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1cj10qhrs9vrg.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:34Z",
      "native_id": "MED:42998045",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42998045"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:3004|Pharmacogenetics and Drug Metabolism",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.",
  "title_text": "Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:34Z",
  "url": "https://research.draconitic.com/paper/1cj10qhrs9vrg",
  "venue": "Clinical pharmacology and therapeutics",
  "versions": []
}