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dc.contributor.authorBoeree, Martin J
dc.contributor.authorDiacon, Andreas H
dc.contributor.authorDawson, Rodney
dc.contributor.authorNarunsky, Kim
dc.contributor.authordu Bois, Jeannine
dc.contributor.authorVenter, Amour
dc.contributor.authorPhillips, Patrick P J
dc.contributor.authorGillespie, Stephen H
dc.contributor.authorMc Hugh, Timothy D
dc.contributor.authorHoelscher, Michael
dc.contributor.authorHeinrich, Norbert
dc.contributor.authorRehal, Sunita
dc.contributor.authorvan Soolingen, Dick
dc.contributor.authorvan Ingen, Jakko
dc.contributor.authorMagis-Escurra, Cecile
dc.contributor.authorBurger, David
dc.contributor.authorPlemper van Balen, Georgette
dc.contributor.authorAarnoutse, Rob E
dc.contributor.authorPanACEA Consortium
dc.date.accessioned2016-03-22T10:00:03Z
dc.date.available2016-03-22T10:00:03Z
dc.date.issued2015-05-01
dc.identifier.citationBoeree , M J , Diacon , A H , Dawson , R , Narunsky , K , du Bois , J , Venter , A , Phillips , P P J , Gillespie , S H , Mc Hugh , T D , Hoelscher , M , Heinrich , N , Rehal , S , van Soolingen , D , van Ingen , J , Magis-Escurra , C , Burger , D , Plemper van Balen , G , Aarnoutse , R E & PanACEA Consortium 2015 , ' A dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosis ' , American Journal of Respiratory and Critical Care Medicine , vol. 191 , no. 9 , pp. 1058-1065 . https://doi.org/10.1164/rccm.201407-1264OCen
dc.identifier.issn1073-449X
dc.identifier.otherPURE: 167131622
dc.identifier.otherPURE UUID: a06c9247-ec49-4866-8beb-745af40e432c
dc.identifier.otherPubMed: 25654354
dc.identifier.otherScopus: 84924312172
dc.identifier.otherORCID: /0000-0001-6537-7712/work/39477882
dc.identifier.otherWOS: 000353840800015
dc.identifier.urihttp://hdl.handle.net/10023/8455
dc.descriptionThe study was funded by the EDCTP (European & Developing Countries Clinical Trials Partnership), NACCAP (Netherlands-African partnership for Capacity development and Clinical interventions Against Poverty-related diseases) and the Bill & Melinda Gates Foundation.en
dc.description.abstractRationale: Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment. Objectives: To evaluate the safety and tolerability, the pharmacokinetics and the extended early bactericidal activity of increasing doses of rifampin. Methods: Patients with drug-susceptible tuberculosis were enrolled into a control group of 8 patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20 mg/kg, 25 mg/kg, 30 mg/kg and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed. Measurements and Main Results: Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were 5 grade 3 events of which 1 was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10CFU/ml sputum in the 10, 20, 25, 30 and 35 mg/kg groups respectively. Conclusions: Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a non-linear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registration available at www.clinicaltrials.gove, ID NCT01392911.
dc.language.isoeng
dc.relation.ispartofAmerican Journal of Respiratory and Critical Care Medicineen
dc.rights© 2015, Publisher / the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.atsjournals.org / https://dx.doi.org/10.1164/rccm.201407-1264OCen
dc.subjectTuberculosisen
dc.subjectClinical trialen
dc.subjectRifampicinen
dc.subjectGlobal healthen
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectNDASen
dc.subjectBDCen
dc.subjectR2Cen
dc.subject~DC~en
dc.subject.lccRMen
dc.titleA dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosisen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Global Health Implementation Groupen
dc.contributor.institutionUniversity of St Andrews.Gillespie Groupen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.Infection Groupen
dc.identifier.doihttps://doi.org/10.1164/rccm.201407-1264OC
dc.description.statusPeer revieweden


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