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dc.contributor.authorSvensson, Elin M
dc.contributor.authorSvensson, Robin J
dc.contributor.authorTe Brake, Lindsey H M
dc.contributor.authorBoeree, Martin J
dc.contributor.authorHeinrich, Norbert
dc.contributor.authorKonsten, Sarah
dc.contributor.authorChurchyard, Gavin
dc.contributor.authorDawson, Rodney
dc.contributor.authorDiacon, Andreas H
dc.contributor.authorKibiki, Gibson S
dc.contributor.authorMinja, Lilian T
dc.contributor.authorNtingiya, Nyanda E
dc.contributor.authorSanne, Ian
dc.contributor.authorGillespie, Stephen H
dc.contributor.authorHoelscher, Michael
dc.contributor.authorPhillips, Patrick P J
dc.contributor.authorSimonsson, Ulrika S H
dc.contributor.authorAarnoutse, Rob
dc.date.accessioned2018-06-28T15:30:07Z
dc.date.available2018-06-28T15:30:07Z
dc.date.issued2018-06-18
dc.identifier.citationSvensson , E M , Svensson , R J , Te Brake , L H M , Boeree , M J , Heinrich , N , Konsten , S , Churchyard , G , Dawson , R , Diacon , A H , Kibiki , G S , Minja , L T , Ntingiya , N E , Sanne , I , Gillespie , S H , Hoelscher , M , Phillips , P P J , Simonsson , U S H & Aarnoutse , R 2018 , ' The potential for treatment shortening with higher rifampicin doses : relating drug exposure to treatment response in patients with pulmonary tuberculosis ' , Clinical Infectious Diseases , vol. 67 , no. 1 , pp. 34-41 . https://doi.org/10.1093/cid/ciy026en
dc.identifier.issn1058-4838
dc.identifier.otherPURE: 253439939
dc.identifier.otherPURE UUID: 1024bb3c-0720-470c-adc2-85873891370b
dc.identifier.otherPubMed: 29917079
dc.identifier.otherPubMedCentral: PMC6005123
dc.identifier.otherORCID: /0000-0001-6537-7712/work/46152090
dc.identifier.otherScopus: 85055439604
dc.identifier.otherWOS: 000438446600010
dc.identifier.urihttp://hdl.handle.net/10023/14724
dc.descriptionThis work was supported by the European and Developing Countries Clinical Trials partnership (grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013) and the German Ministry for Education and Research (grant 01KA0901). The original study conducted within the PanACEA consortium.en
dc.description.abstractBackground: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results: Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions: Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.
dc.format.extent8
dc.language.isoeng
dc.relation.ispartofClinical Infectious Diseasesen
dc.rights© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/ciy026en
dc.subjectHigh-dose rifampicinen
dc.subjectPharmacometricsen
dc.subjectPK-PDen
dc.subjectExposure-responseen
dc.subjectSputum culture conversionen
dc.subjectRA0421 Public health. Hygiene. Preventive Medicineen
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectNDASen
dc.subject.lccRA0421en
dc.subject.lccRMen
dc.titleThe potential for treatment shortening with higher rifampicin doses : relating drug exposure to treatment response in patients with pulmonary tuberculosisen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.Infection and Global Health Divisionen
dc.contributor.institutionUniversity of St Andrews.Global Health Implementation Groupen
dc.contributor.institutionUniversity of St Andrews.Gillespie Groupen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.Infection Groupen
dc.identifier.doihttps://doi.org/10.1093/cid/ciy026
dc.description.statusPeer revieweden


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