{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:07:48Z","timestamp":1780459668612,"version":"3.54.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a crossover pharmacokinetic trial in children aged \u22645 years receiving levofloxacin RR-TB preventive therapy. Pharmacokinetic sampling was done after 15\u201320 mg\/kg doses of levofloxacin with 100 mg dispersible and crushed 250 mg non-dispersible levofloxacin formulations. A population pharmacokinetic model was developed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Twenty-five children were included, median (IQR) weight and age 12.2 (10.7\u201315.0) kg and 2.56 (1.58\u20134.03) years, respectively. A two-compartment model with first-order elimination and transit compartment absorption best described levofloxacin pharmacokinetics. Allometric scaling adjusted for body size, and maturation of clearance with age was characterized. Typical clearance in a 12 kg child was estimated at 4.17 L\/h. Non-dispersible tablets had 21.5% reduced bioavailability compared with the dispersible formulation, with no significant differences in other absorption parameters.<\/jats:p>\n                  <jats:p>Dosing simulations showed that current recommended dosing for both formulations result in median exposures below adult-equivalent exposures at a 750 mg daily dose, mainly in children &amp;gt;6 months. Higher levofloxacin doses of 16\u201330 mg\/kg for dispersible and 20\u201338 mg\/kg for crushed non-dispersible tablets may be required in children &amp;gt;6 months.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The dispersible paediatric levofloxacin formulation has improved bioavailability compared with the crushed non-dispersible adult formulation, but exposures remain below those in adults. We propose optimized age- and weight-based dosing for levofloxacin, which require further evaluation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkad257","type":"journal-article","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T13:16:09Z","timestamp":1692450969000},"page":"2481-2488","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacokinetics and optimized dosing of dispersible and non-dispersible levofloxacin formulations in young children"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-7477","authenticated-orcid":false,"given":"Louvina E","family":"van der Laan","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"},{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke C","family":"Hesseling","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5755-4133","authenticated-orcid":false,"given":"H Simon","family":"Schaaf","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Palmer","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather R","family":"Draper","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":false,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":false,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-1950","authenticated-orcid":false,"given":"Anthony J","family":"Garcia-Prats","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"},{"name":"University of Wisconsin-Madison, School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"2023100302090404300_dkad257-B1","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/S1473-3099(16)30132-3","article-title":"Global burden of drug-resistant tuberculosis in children: a mathematical modelling study","volume":"16","author":"Dodd","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"2023100302090404300_dkad257-B2","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/S0140-6736(14)60195-1","article-title":"Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates","volume":"383","author":"Jenkins","year":"2014","journal-title":"Lancet"},{"key":"2023100302090404300_dkad257-B3","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1093\/cid\/ciz502","article-title":"TB preventive therapy for individuals exposed to drug-resistant tuberculosis: feasibility and safety of a community-based delivery of fluoroquinolone-containing preventive regimen","volume":"70","author":"Malik","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2023100302090404300_dkad257-B4","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1093\/cid\/cit655","article-title":"Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study","volume":"57","author":"Seddon","year":"2013","journal-title":"Clin Infect Dis"},{"key":"2023100302090404300_dkad257-B5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.tube.2011.11.001","article-title":"Paediatric use of second-line anti-tuberculosis agents: a review","volume":"92","author":"Seddon","year":"2012","journal-title":"Tuberculosis"},{"key":"2023100302090404300_dkad257-B6","doi-asserted-by":"crossref","first-page":"e01865-","DOI":"10.1128\/AAC.01865-18","article-title":"Pharmacokinetics, safety, and dosing of novel pediatric levofloxacin dispersible tablets in children with multidrug-resistant tuberculosis exposure","volume":"63","author":"Garcia-Prats","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023100302090404300_dkad257-B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13063-018-3070-0","article-title":"Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)","volume":"19","author":"Seddon","year":"2018","journal-title":"Trials"},{"key":"2023100302090404300_dkad257-B8","author":"U.S. Food and Drug Administration","year":"2008"},{"key":"2023100302090404300_dkad257-B9","doi-asserted-by":"crossref","first-page":"e01521-","DOI":"10.1128\/AAC.01521-17","article-title":"Levofloxacin population pharmacokinetics in South African children treated for multidrug-resistant tuberculosis","volume":"62","author":"Denti","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023100302090404300_dkad257-B10","doi-asserted-by":"crossref","first-page":"e50","DOI":"10.1038\/psp.2013.24","article-title":"Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose","volume":"2","author":"Keizer","year":"2013","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2023100302090404300_dkad257-B11","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s10928-007-9066-0","article-title":"Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies","volume":"34","author":"Savic","year":"2007","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2023100302090404300_dkad257-B12","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1023\/A:1012299115260","article-title":"Ways to fit a PK model with some data below the quantification limit","volume":"28","author":"Beal","year":"2001","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2023100302090404300_dkad257-B13","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev.pharmtox.48.113006.094708","article-title":"Mechanism-based concepts of size and maturity in pharmacokinetics","volume":"48","author":"Anderson","year":"2008","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2023100302090404300_dkad257-B14","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1002\/jps.23574","article-title":"A pharmacokinetic standard for babies and adults","volume":"102","author":"Holford","year":"2013","journal-title":"J Pharm Sci"},{"key":"2023100302090404300_dkad257-B15","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2133\/dmpk.24.25","article-title":"Mechanistic basis of using body size and maturation to predict clearance in humans","volume":"24","author":"Anderson","year":"2009","journal-title":"Drug Metab Pharmacokinet"},{"key":"2023100302090404300_dkad257-B16","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1007\/BF00866487","article-title":"Does kL\/PCr estimate GFR, or does GFR determine k?","volume":"6","author":"Schwartz","year":"1992","journal-title":"Pediatr Nephrol"},{"key":"2023100302090404300_dkad257-B17","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1038\/sj.ki.5000385","article-title":"Glomerular filtration rate via plasma iohexol disappearance: pilot study for chronic kidney disease in children","volume":"69","author":"Schwartz","year":"2006","journal-title":"Kidney Int"},{"key":"2023100302090404300_dkad257-B18","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":"Wasmann","year":"2021","journal-title":"Br J Clin Pharmacol"},{"key":"2023100302090404300_dkad257-B19","doi-asserted-by":"crossref","first-page":"e00770-18","DOI":"10.1128\/AAC.00770-18","article-title":"Increased doses lead to higher drug exposures of levofloxacin for treatment of tuberculosis","volume":"62","author":"Peloquin","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023100302090404300_dkad257-B20","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":"Al-Sallami","year":"2015","journal-title":"Clin Pharmacokinet"},{"key":"2023100302090404300_dkad257-B21","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1128\/AAC.01036-07","article-title":"Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis","volume":"52","author":"Peloquin","year":"2008","journal-title":"Antimicrobial Agents"},{"key":"2023100302090404300_dkad257-B22","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1248\/bpb.18.315","article-title":"Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases","volume":"18","author":"Tanigawara","year":"1995","journal-title":"Biol Pharm Bull"},{"key":"2023100302090404300_dkad257-B23","doi-asserted-by":"crossref","first-page":"3244","DOI":"10.1128\/AAC.00064-11","article-title":"Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis","volume":"55","author":"Thwaites","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2023100302090404300_dkad257-B24","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1128\/AAC.42.5.1098","article-title":"Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection","volume":"42","author":"Preston","year":"1998","journal-title":"Antimicrob Agents Chemother"},{"key":"2023100302090404300_dkad257-B25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1097\/INF.0000000000001022","article-title":"Pharmacokinetics and dosing of levofloxacin in children treated for active or latent multidrug-resistant tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands","volume":"35","author":"Mase","year":"2016","journal-title":"Pediatr Infect Dis J"},{"key":"2023100302090404300_dkad257-B26","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1093\/cid\/ciy416","article-title":"Clinical and cardiac safety of long-term levofloxacin in children treated for multidrug-resistant tuberculosis","volume":"67","author":"Garcia-Prats","year":"2018","journal-title":"Clin Infect Dis"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/10\/2481\/51743406\/dkad257.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/78\/10\/2481\/51743406\/dkad257.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T02:09:42Z","timestamp":1696298982000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/78\/10\/2481\/7246312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,19]]},"references-count":26,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,8,19]]},"published-print":{"date-parts":[[2023,10,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkad257","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,10]]},"published":{"date-parts":[[2023,8,19]]}}}