{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:45:48Z","timestamp":1787237148883,"version":"build-2736575974"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T00:00:00Z","timestamp":1700524800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"\n Background<\/jats:title>\n The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.<\/jats:p>\n <\/jats:sec>\n \n Methods and findings<\/jats:title>\n We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics.<\/jats:p>\n \n Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%];\n p<\/jats:italic>\n < 0.001) and 64.5% (95% CI [52.1%, 78.9%];\n p<\/jats:italic>\n < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%];\n p<\/jats:italic>\n < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%];\n p<\/jats:italic>\n < 0.001) in children on lopinavir\/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%];\n p<\/jats:italic>\n < 0.001) when simultaneously coadministered with lopinavir\/ritonavir and was 37% lower (95% CI [22%, 52%];\n p<\/jats:italic>\n < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug\u2013drug interactions with lopinavir\/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n \n ClinicalTrials.gov registration numbers;\n NCT02348177<\/jats:ext-link>\n ,\n NCT01637558<\/jats:ext-link>\n ,\n ISRCTN63579542<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pmed.1004303","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T13:34:49Z","timestamp":1700573689000},"page":"e1004303","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4491-4256","authenticated-orcid":true,"given":"Lufina Tsirizani","family":"Galileya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-8150","authenticated-orcid":true,"given":"Roeland E.","family":"Wasmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5551-5752","authenticated-orcid":true,"given":"Chishala","family":"Chabala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Rabie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3699-1841","authenticated-orcid":true,"given":"Irene","family":"Njahira Mukui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"Hesseling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-759X","authenticated-orcid":true,"given":"Heather","family":"Zar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Aarnoutse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7008-4145","authenticated-orcid":true,"given":"Anna","family":"Turkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9738-5490","authenticated-orcid":true,"given":"Diana","family":"Gibb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2559-6034","authenticated-orcid":true,"given":"Mark F.","family":"Cotton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0982-6226","authenticated-orcid":true,"given":"Helen","family":"McIlleron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":true,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,11,21]]},"reference":[{"key":"pmed.1004303.ref001","author":"World Health Organization (WHO).","year":"2021","journal-title":"Global Tuberculosis Report 2021."},{"issue":"2","key":"pmed.1004303.ref002","first-page":"553","article-title":"Tuberculosis in Infants and Children.","volume":"5","author":"GS Lamb","year":"2017","journal-title":"Microbiol Spectra"},{"issue":"s3","key":"pmed.1004303.ref003","doi-asserted-by":"crossref","first-page":"S201","DOI":"10.1086\/651492","article-title":"HIV Infection\u2013Associated Tuberculosis: The Epidemiology and the Response","volume":"50","author":"H Getahun","year":"2010","journal-title":"Clin Infect Dis"},{"key":"pmed.1004303.ref004","author":"World Health Organization (WHO)","year":"2010","journal-title":"Rapid advice: treatment of tuberculosis in children"},{"issue":"6","key":"pmed.1004303.ref005","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s40262-018-0716-8","article-title":"A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs","volume":"58","author":"A Daskapan","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"pmed.1004303.ref006","first-page":"63","article-title":"Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?","volume":"1","author":"C Sekaggya-Wiltshire","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"10","key":"pmed.1004303.ref007","doi-asserted-by":"crossref","first-page":"6050","DOI":"10.1128\/AAC.00480-16","article-title":"HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients","volume":"60","author":"N Rockwood","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"33","key":"pmed.1004303.ref008","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1200\/JCO.2017.73.7916","article-title":"Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement.","volume":"35","author":"ES Kim","year":"2017","journal-title":"J Clin Oncol"},{"issue":"4","key":"pmed.1004303.ref009","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S2213-2600(14)70031-1","article-title":"Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis.","volume":"2","author":"K Dheda","year":"2014","journal-title":"Lancet Respir Med"},{"issue":"2","key":"pmed.1004303.ref010","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1517\/14740338.5.2.231","article-title":"Adverse reactions to first-line antituberculosis drugs.","volume":"5","author":"EJ Forget","year":"2006","journal-title":"Expert Opin Drug Saf."},{"issue":"1","key":"pmed.1004303.ref011","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/s13063-018-2608-5","article-title":"Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial.","volume":"19","author":"C Chabala","year":"2018","journal-title":"Trials"},{"issue":"1","key":"pmed.1004303.ref012","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1016\/S2352-3018(18)30293-5","article-title":"Lopinavir\u2013ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir\u2013ritonavir without rifampicin: a pharmacokinetic modelling and clinical study.","volume":"6","author":"H Rabie","year":"2019","journal-title":"Lancet HIV"},{"issue":"1","key":"pmed.1004303.ref013","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/cid\/ciab908","article-title":"Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study","volume":"75","author":"P Denti","year":"2022","journal-title":"Clin Infect Dis"},{"issue":"4","key":"pmed.1004303.ref014","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1128\/AAC.02600-15","article-title":"Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines","volume":"60","author":"A Bekker","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"pmed.1004303.ref015","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/psp.2013.24","article-title":"Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose.","volume":"2","author":"R Keizer","year":"2013","journal-title":"CPT Pharmacometrics Syst Pharmacol."},{"issue":"2","key":"pmed.1004303.ref016","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1208\/s12248-009-9112-5","article-title":"Handling Data Below the Limit of Quantification in Mixed Effect Models.","volume":"11","author":"M Bergstrand","year":"2009","journal-title":"AAPS J."},{"issue":"11","key":"pmed.1004303.ref017","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s40262-015-0277-z","article-title":"Prediction of Fat-Free Mass in Children.","volume":"54","author":"HS Al-Sallami","year":"2015","journal-title":"Clin Pharmacokinet."},{"issue":"5\u20136","key":"pmed.1004303.ref018","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1023\/A:1022972420004","article-title":"Use of prior information to stabilize a population data analysis.","volume":"29","author":"PO Gisleskog","year":"2002","journal-title":"J Pharmacokinet Pharmacodyn."},{"issue":"4","key":"pmed.1004303.ref019","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1002\/cpt.2044","article-title":"Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping","volume":"109","author":"K Gausi","year":"2021","journal-title":"Clin Pharmacol Ther"},{"issue":"3","key":"pmed.1004303.ref020","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1208\/s12248-012-9373-2","article-title":"Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses.","volume":"14","author":"RJ Keizer","year":"2012","journal-title":"AAPS J."},{"issue":"3","key":"pmed.1004303.ref021","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1365-2125.2012.04205.x","article-title":"Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics","volume":"74","author":"E Svensson","year":"2012","journal-title":"Br J Clin Pharmacol"},{"issue":"7","key":"pmed.1004303.ref022","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1111\/bcp.14694","article-title":"Constructing a representative in-silico population for paediatric simulations: Application to HIV-positive African children","volume":"87","author":"RE Wasmann","year":"2021","journal-title":"Br J Clin Pharmacol"},{"issue":"9","key":"pmed.1004303.ref023","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1093\/jac\/dky152","article-title":"Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis","volume":"73","author":"KE Stott","year":"2018","journal-title":"J Antimicrob Chemother"},{"issue":"8","key":"pmed.1004303.ref024","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s40265-014-0222-8","article-title":"Therapeutic Drug Monitoring in the Treatment of Tuberculosis: An Update.","volume":"74","author":"A Alsultan","year":"2014","journal-title":"Drugs"},{"key":"pmed.1004303.ref025","first-page":"548","author":"World Health Organization","year":"2021","journal-title":"Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach."},{"issue":"1","key":"pmed.1004303.ref026","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1124\/pr.110.002857","article-title":"Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake.","volume":"63","author":"M Niemi","year":"2011","journal-title":"Pharmacol Rev."},{"issue":"9","key":"pmed.1004303.ref027","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1128\/AAC.00341-07","article-title":"Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily","volume":"51","author":"EP Acosta","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pmed.1004303.ref028","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3390\/ijms20020294","article-title":"Ginsenoside Rb1 Blocks Ritonavir-Induced Oxidative Stress and eNOS Downregulation through Activation of Estrogen Receptor-Beta and Upregulation of SOD in Human Endothelial Cells.","volume":"20","author":"J-M L\u00fc","year":"2019","journal-title":"Int J Mol Sci."},{"issue":"2","key":"pmed.1004303.ref029","doi-asserted-by":"crossref","DOI":"10.4172\/2161-1068.1000209","article-title":"Current Overview of Anti-Tuberculosis Drugs: Metabolism and Toxicities.","volume":"6","author":"S Sarkar","year":"2016","journal-title":"Mycobact Dis"},{"issue":"1","key":"pmed.1004303.ref030","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.advms.2015.09.007","article-title":"Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update.","volume":"61","author":"M Njire","year":"2016","journal-title":"Adv Med Sci"},{"key":"pmed.1004303.ref031","author":"AbbVie Pharmaceutical Research & Development","year":"2022","journal-title":"Kaletra 80mg\/20mg Oral Solution."},{"issue":"5","key":"pmed.1004303.ref032","first-page":"625","article-title":"Inactivation of isoniazid by condensation in a syrup preparation","volume":"45","author":"KV Rao","year":"1971","journal-title":"Bull World Health Organ"},{"issue":"3","key":"pmed.1004303.ref033","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/jps.20765","article-title":"Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Isoniazid**A project of the International Pharmaceutical Federation FIP, Groupe BCS, www.fip.org\/bcs.","volume":"96","author":"C Becker","year":"2007","journal-title":"J Pharm Sci"},{"key":"pmed.1004303.ref034","first-page":"7719","article-title":"Effect of efavirenz-based antiretroviral therapy and high-dose rifampicin on the pharmacokinetics of isoniazid and acetyl-isoniazid","volume":"7800","author":"MT Chirehwa","year":"2018","journal-title":"J Antimicrob Chemother"},{"issue":"5","key":"pmed.1004303.ref035","doi-asserted-by":"crossref","first-page":"666","DOI":"10.5588\/ijtld.15.0288","article-title":"Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol","volume":"20","author":"A Mukherjee","year":"2016","journal-title":"HIV-infected Indian children. Int J Tuberc Lung Dis"},{"issue":"2","key":"pmed.1004303.ref036","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1128\/AAC.50.2.407-413.2006","article-title":"Low Levels of Pyrazinamide and Ethambutol in Children with Tuberculosis and Impact of Age, Nutritional Status, and Human Immunodeficiency Virus Infection","volume":"50","author":"SM Graham","year":"2006","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pmed.1004303.ref037","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01701-16","article-title":"Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection","volume":"61","author":"S Antwi","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"issue":"5","key":"pmed.1004303.ref038","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1097\/INF.0000000000001069","article-title":"Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status","volume":"35","author":"G Ramachandran","year":"2016","journal-title":"Pediatr Infect Dis J"},{"key":"pmed.1004303.ref039","article-title":"Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization\u2013Recommended Weight Band Doses and Formulations","author":"C Chabala","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"1","key":"pmed.1004303.ref040","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S2352-4642(21)00302-3","article-title":"One dose does not fit all: revising the WHO paediatric dosing tool to include the non-linear effect of body size and maturation","volume":"6","author":"P Denti","year":"2022","journal-title":"Lancet Child Adolesc Health"},{"issue":"12","key":"pmed.1004303.ref041","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.1093\/jac\/dkab336","article-title":"Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial","volume":"76","author":"AJ Garcia-Prats","year":"2021","journal-title":"J Antimicrob Chemother"},{"issue":"1","key":"pmed.1004303.ref042","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1183\/09031936.00177014","article-title":"An interlaboratory quality control programme for the measurement of tuberculosis drugs","volume":"46","author":"RE Aarnoutse","year":"2015","journal-title":"Eur Respir J"},{"issue":"3","key":"pmed.1004303.ref043","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":"F Gafar","year":"2023","journal-title":"Eur Respir J"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1004303","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T13:35:17Z","timestamp":1700573717000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1004303"}},"subtitle":[],"editor":[{"given":"Marie-Louise","family":"Newell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,11,21]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1004303","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,21]]}}}