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dc.contributor.authorSvensson, Robin J
dc.contributor.authorSvensson, Elin M
dc.contributor.authorAarnoutse, Rob E
dc.contributor.authorDiacon, Andreas H
dc.contributor.authorDawson, Rodney
dc.contributor.authorGillespie, Stephen H
dc.contributor.authorMoodley, Mischka
dc.contributor.authorBoeree, Martin J
dc.contributor.authorSimonsson, Ulrika S H
dc.date.accessioned2019-04-27T23:38:02Z
dc.date.available2019-04-27T23:38:02Z
dc.date.issued2018-04-28
dc.identifier.citationSvensson , R J , Svensson , E M , Aarnoutse , R E , Diacon , A H , Dawson , R , Gillespie , S H , Moodley , M , Boeree , M J & Simonsson , U S H 2018 , ' Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations ' , Journal of Infectious Diseases , vol. In press . https://doi.org/10.1093/infdis/jiy242en
dc.identifier.issn0022-1899
dc.identifier.otherPURE: 253233657
dc.identifier.otherPURE UUID: d96cb9d5-4e9e-4437-ab64-a8181d5b5e43
dc.identifier.otherPubMed: 29718390
dc.identifier.otherScopus: 85055426974
dc.identifier.otherORCID: /0000-0001-6537-7712/work/45366208
dc.identifier.otherWOS: 000441792600017
dc.identifier.urihttp://hdl.handle.net/10023/17599
dc.descriptionThis work was supported by the Swedish Research Council (grant 521-2011-3442 to R. J. S. and U. S. H. S.), the Innovative Medicines Initiative Joint Undertaking (award 115337, with contribution from the European Union’s Seventh Framework Programme [FP7/2007–2013] and the European Federation of Pharmaceutical Industries and Associations [in-kind contribution]), the European and Developing Countries Clinical Trials Partnership (awards IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013), the Netherlands-African Partnership for Capacity Development and Clinical Interventions Against Poverty-Related Diseases, and the Bill and Melinda Gates Foundation.en
dc.description.abstractBackground The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin. Methods Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates. Results The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25–10.3 days. Conclusions A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.
dc.language.isoeng
dc.relation.ispartofJournal of Infectious Diseasesen
dc.rights© 2018, the Author(s). This work has been made available online in accordance with the publisher’s policies. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1093/infdis/jiy242en
dc.subjectPharmacodynamicsen
dc.subjectTuberculosisen
dc.subjectPharmacokineticsen
dc.subjectPatientsen
dc.subjectTime to positivityen
dc.subjectEarly bactericidal effecten
dc.subjectMycobacterium tuberculosisen
dc.subjectRA0421 Public health. Hygiene. Preventive Medicineen
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectNDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccRA0421en
dc.subject.lccRMen
dc.titleGreater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulationsen
dc.typeJournal articleen
dc.contributor.sponsorEuropean Commissionen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
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. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. Infection Groupen
dc.identifier.doihttps://doi.org/10.1093/infdis/jiy242
dc.description.statusPeer revieweden
dc.date.embargoedUntil2019-04-28
dc.identifier.grantnumberen


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