{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:17:05Z","timestamp":1788369425295,"version":"build-2803163510"},"reference-count":56,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1U01AI134585-01A1"],"award-info":[{"award-number":["1U01AI134585-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Metformin is under investigation as adjunctive host-directed therapy for tuberculosis (TB), which might interact with first-line TB treatment. We used population pharmacokinetic modeling to assess whether metformin alters first-line TB-drug pharmacokinetics in HIV\/TB-coinfected adults without diabetes. Rifampicin, isoniazid, and pyrazinamide pharmacokinetics were investigated in participants from a randomized clinical trial of adjunctive metformin (500 mg twice daily to week 12) in adults starting HIV-associated TB treatment. Antiretroviral therapy (ART)-na\u00efve participants initiated dolutegravir-based ART within 8 weeks. Intensive and semi-intensive sampling was conducted at week 5; concentration\u2013time data were analyzed using non-linear mixed-effects modeling. Data from 78 individuals (43 receiving metformin, median weight 60.8 kg, 62.8% male, 79.5% on ART) were analyzed. Rifampicin and pyrazinamide were described by one-compartment models with linear elimination; typical clearances were 15.8 L\/h (95% CI: 13.5\u201318.7) and 3.88 L\/h (95% CI: 3.54\u20134.08), respectively. Isoniazid followed a two-compartment model with a mixture model for acetylator status; clearance was 10.5 L\/h (95% CI: 9.44\u201311.9) in slow acetylators and 28.8 L\/h (95% CI: 25.6\u201331.0) in fast\/intermediate acetylators. Metformin reduced isoniazid bioavailability by 15.6% (95% CI: 4.45\u201326.4%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.009) and rifampicin bioavailability by 24.0% (95% CI: 7.83\u201336.3%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.007), decreasing the area under the curve from 0 to 24 h from 18.2 to 15.6 mg\u00b7h\/L and from 35.9 to 27.1 mg\u00b7h\/L, respectively. No significant effect on pyrazinamide was detected. We found that non-diabetic patients on metformin had lower isoniazid and rifampicin bioavailability. Lowered rifampicin exposure might be clinically relevant; simulations suggest that this could be offset by a single 150 mg rifampicin dose.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>CLINICAL TRIALS<\/jats:title>\n                      <jats:p>\n                        This study is registered with ClinicalTrials.gov as\n                        <jats:related-object xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" document-id=\"NCT04930744\" document-id-type=\"clinical-trial-number\" source-id=\"ClinicalTrials.gov\" source-id-type=\"registry-name\" source-type=\"clinical-trials-registry\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04930744\">NCT04930744<\/jats:related-object>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00748-26","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T13:00:29Z","timestamp":1786021229000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["The effect of metformin on the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in adults with tuberculosis"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3401-8829","authenticated-orcid":true,"given":"Jacques","family":"Rossouw","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Wallis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tcy5w98","id-type":"ROR","asserted-by":"publisher"}],"name":"The Aurum Institute","place":["Johannesburg, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8970-7306","authenticated-orcid":true,"given":"Hardy","family":"Kornfeld","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, UMass Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-8798","authenticated-orcid":true,"given":"Amit","family":"Singhal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"A*STAR Infectious Diseases Labs, Agency for Science Technology and Research (A*STAR)","place":["Singapore, Republic of Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-6606","authenticated-orcid":true,"given":"Gary","family":"Maartens","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":true,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":true,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-8150","authenticated-orcid":true,"given":"Roeland E.","family":"Wasmann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"World Health Organization. 2025. 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StatPearls. Available from: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12588714. Retrieved 21 Jan 2026."},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv394"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000000983"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00748-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00748-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:54:51Z","timestamp":1788368091000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00748-26"}},"subtitle":[],"editor":[{"given":"Sean","family":"Wasserman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":56,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,2]]}},"alternative-id":["10.1128\/aac.00748-26"],"URL":"https:\/\/doi.org\/10.1128\/aac.00748-26","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"assertion":[{"value":"2026-05-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00748-26"}}