{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:58:52Z","timestamp":1785560332293,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003399","name":"Shanghai Municipal Science and Technology Commission 2025 Key Technology R&D Program \u201cMedical Innovation Research\u201d Project","doi-asserted-by":"publisher","award":["25Y32800100"],"award-info":[{"award-number":["25Y32800100"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82574166"],"award-info":[{"award-number":["82574166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82574166"],"award-info":[{"award-number":["82574166"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Isoniazid (INH) remains a cornerstone of tuberculosis (TB) prevention and treatment, administered either as monotherapy or in combination with rifamycin-containing regimens. In this study, the preventive regimens analyzed included 6 months of daily INH monotherapy (6H), 3 months of daily INH plus rifampicin (3HR), and 3 months of twice-weekly INH plus rifapentine (3H2P2). Despite the adoption of shorter-course regimens, substantial inter-individual variability (IIV) in INH exposure persists, potentially impacting both therapeutic efficacy and toxicity. A quantitative, regimen-specific characterization of INH pharmacokinetics is therefore critical to support model-informed dosing strategies. Methods: Population pharmacokinetic models were developed separately for INH administered as 6H, 3HR, and 3H2P2. The models characterized absorption, clearance, and IIV of INH, while accounting for co-administered rifamycin. The effects of N-acetyltransferase 2 (NAT2) acetylator phenotype and relevant clinical covariates were systematically evaluated. Model performance was assessed using goodness-of-fit diagnostics, posterior predictive checks, and visual predictive checks. Population pharmacokinetic models were developed using a Bayesian nonlinear mixed-effects framework implemented in Stan through CmdStanR version 0.9.0, with additional data processing, statistical summaries, and visualization performed using R version 4.2.3. Results: INH pharmacokinetics were adequately described by regimen-specific models, revealing distinct differences in absorption and variability across regimens. Typical INH apparent oral clearance (CL\/F) estimates were 21.83 L\/h for 6H, 26.32 L\/h for 3HR, and 25.98 L\/h for 3H2P2. NAT2 phenotype was a major determinant of INH clearance across regimens: compared with intermediate acetylators, slow acetylators showed 35.4% lower CL\/F, whereas fast acetylators showed 48.4% higher CL\/F, indicating higher INH exposure in slow acetylators and lower exposure in fast acetylators. Body weight also influenced INH pharmacokinetics. Co-administration with rifampicin or rifapentine influenced INH pharmacokinetics in a manner consistent with reduced exposure in rifamycin-containing regimens, particularly among fast acetylators. Conclusions: Regimen-specific population pharmacokinetic modeling elucidated clinically relevant differences in INH exposure across commonly used preventive and treatment regimens. These findings highlight the importance of accounting for regimen- and genotype-specific effects when optimizing INH dosing and provide a quantitative framework for future model-informed precision dosing approaches in TB care.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080937","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:32:13Z","timestamp":1785403933000},"page":"937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regimen-Specific Population Pharmacokinetics of Isoniazid with and Without Rifamycin: A Bayesian Modeling Analysis of 6H, 3HR, and 3H2P2 Regimens"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhipeng","family":"Li","sequence":"first","affiliation":[{"name":"Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Xu","sequence":"additional","affiliation":[{"name":"Fengxian District Center for Disease Control and Prevention, Fengxian District, Shanghai 201499, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lexian","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuliang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1056\/NEJMoa1104875","article-title":"Three Months of Rifapentine and Isoniazid for Latent Tuberculosis Infection","volume":"365","author":"Sterling","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_2","unstructured":"World Health Organization (2023, September 20). Latent Tuberculosis Infection: Updated and Consolidated Guidelines for Programmatic Management. Available online: https:\/\/iris.who.int\/handle\/10665\/260233."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1056\/NEJMoa1806808","article-title":"One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis","volume":"380","author":"Swindells","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Durovni, B., Cordeiro-Santos, M., Cavalcante, S.C., Spener-Gomes, R., Garcia, J., Cohn, S., Saraceni, V., Kohler, B., Moulton, L.H., and Brito da Souza, A. (2026). Acceptability and Safety of One versus Three Months of Rifapentine and Isoniazid to Prevent Tuberculosis in People Exposed in the Household or Workplace in Brazil: The Ultra-Curto Randomized Controlled Trial. PLoS Med., 23.","DOI":"10.1371\/journal.pmed.1004758"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2201596","DOI":"10.1183\/13993003.01596-2022","article-title":"Global Estimates and Determinants of Antituberculosis Drug Pharmacokinetics in Children and Adolescents: A Systematic Review and Individual Patient Data Meta-Analysis","volume":"61","author":"Gafar","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"BSR20180845","DOI":"10.1042\/BSR20180845","article-title":"Pharmacogenetic Association between NAT2 Gene Polymorphisms and Isoniazid Induced Hepatotoxicity: Trial Sequence Meta-Analysis as Evidence","volume":"39","author":"Khan","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e0170521","DOI":"10.1128\/AAC.01705-21","article-title":"Comparative Efficacy of Rifapentine Alone and in Combination with Isoniazid for Latent Tuberculosis Infection: A Translational Pharmacokinetic-Pharmacodynamic Modeling Study","volume":"65","author":"Radtke","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"268","DOI":"10.2174\/0115734064260853230926080134","article-title":"An Overview of Various Rifampicin Analogs against Mycobacterium Tuberculosis and Their Drug Interactions","volume":"20","author":"Asif","year":"2024","journal-title":"Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105883","DOI":"10.1016\/j.meegid.2026.105883","article-title":"Population Pharmacokinetics of Isoniazid in Adult Indian Tuberculosis Patients: Evaluation of NAT2 Polymorphisms","volume":"138","author":"Thomas","year":"2026","journal-title":"Infect. Genet. Evol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1007\/s00228-022-03362-7","article-title":"Influence of N-Acetyltransferase 2 (NAT2) Genotype\/Single Nucleotide Polymorphisms on Clearance of Isoniazid in Tuberculosis Patients: A Systematic Review of Population Pharmacokinetic Models","volume":"78","author":"Thomas","year":"2022","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.2165\/00003495-200262150-00001","article-title":"Therapeutic Drug Monitoring in the Treatment of Tuberculosis","volume":"62","author":"Peloquin","year":"2002","journal-title":"Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s10928-008-9094-4","article-title":"Likelihood Based Approaches to Handling Data below the Quantification Limit Using NONMEM VI","volume":"35","author":"Ahn","year":"2008","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107827","DOI":"10.1016\/j.ijantimicag.2026.107827","article-title":"The Need for Systematic Therapeutic Drug Monitoring of Isoniazid in Tuberculosis: A Real-World Study","volume":"67","author":"Chancel","year":"2026","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, B., Shi, H.-Q., Feng, M.R., Wang, X.-H., Cao, X.-M., and Cai, W.-M. (2022). Population Pharmacokinetics and Pharmacodynamics of Isoniazid and Its Metabolite Acetylisoniazid in Chinese Population. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.932686"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/phar.2672","article-title":"Systematic Review of Drug-Drug Interactions between Rifamycins and Anticoagulant and Antiplatelet Agents and Considerations for Management","volume":"42","author":"MacDougall","year":"2022","journal-title":"Pharmacotherapy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12565","DOI":"10.1038\/s41598-020-69228-z","article-title":"Hepatocytic Transcriptional Signatures Predict Comparative Drug Interaction Potential of Rifamycin Antibiotics","volume":"10","author":"Dyavar","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1128\/AAC.49.5.1733-1738.2005","article-title":"Should We Use N-Acetyltransferase Type 2 Genotyping to Personalize Isoniazid Doses?","volume":"49","author":"Jetter","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/17512433.2023.2196401","article-title":"Parametric Population Pharmacokinetics of Isoniazid: A Systematic Review","volume":"16","author":"Li","year":"2023","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e01736-19","DOI":"10.1128\/AAC.01736-19","article-title":"Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China","volume":"64","author":"Jing","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"293","DOI":"10.5588\/ijtld.18.0324","article-title":"NAT2 Variants and Toxicity Related to Anti-Tuberculosis Agents: A Systematic Review and Meta-Analysis","volume":"23","author":"Richardson","year":"2019","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e13795","DOI":"10.1111\/cts.13795","article-title":"Efficacy, Safety, and Pharmacokinetics of Isoniazid Affected by NAT2 Polymorphisms in Patients with Tuberculosis: A Systematic Review","volume":"17","author":"Surarak","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/bcp.13846","article-title":"Optimization of Dosing Regimens of Isoniazid and Rifampicin in Children with Tuberculosis in India","volume":"85","author":"Aruldhas","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e00008-18","DOI":"10.1128\/AAC.00008-18","article-title":"Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations","volume":"62","author":"Horita","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s40262-024-01442-8","article-title":"Clinical Pharmacokinetics of Antitubercular Drugs in the Overweight and Obese Population: Implications for Dosage Adjustments","volume":"64","author":"Prager","year":"2025","journal-title":"Clin. Pharmacokinet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5433","DOI":"10.2147\/DDDT.S87131","article-title":"A Proposal for an Individualized Pharmacogenetic-Guided Isoniazid Dosage Regimen for Patients with Tuberculosis","volume":"9","author":"Jung","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e0227721","DOI":"10.1128\/aac.02277-21","article-title":"Effects of Enzyme Induction and Polymorphism on the Pharmacokinetics of Isoniazid and Rifampin in Tuberculosis\/HIV Patients","volume":"66","author":"Sundell","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/FPC.0000000000000552","article-title":"Pharmacogenetics of Tuberculosis Treatment Toxicity and Effectiveness in a Large Brazilian Cohort","volume":"35","author":"Amorim","year":"2025","journal-title":"Pharmacogenet. Genom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/infdis\/jiaf511","article-title":"NAT2 Polymorphisms and Antituberculosis-Induced Hepatotoxicity in Thai People Living with HIV: Insights from a Pharmacogenetic-Pharmacokinetic Cohort Study","volume":"233","author":"Hiranburana","year":"2026","journal-title":"J. Infect. Dis."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/937\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:27:37Z","timestamp":1785558457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":28,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18080937"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18080937","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}