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Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations
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dc.contributor.author | Svensson, Robin J | |
dc.contributor.author | Svensson, Elin M | |
dc.contributor.author | Aarnoutse, Rob E | |
dc.contributor.author | Diacon, Andreas H | |
dc.contributor.author | Dawson, Rodney | |
dc.contributor.author | Gillespie, Stephen H | |
dc.contributor.author | Moodley, Mischka | |
dc.contributor.author | Boeree, Martin J | |
dc.contributor.author | Simonsson, Ulrika S H | |
dc.date.accessioned | 2019-04-27T23:38:02Z | |
dc.date.available | 2019-04-27T23:38:02Z | |
dc.date.issued | 2018-04-28 | |
dc.identifier | 253233657 | |
dc.identifier | d96cb9d5-4e9e-4437-ab64-a8181d5b5e43 | |
dc.identifier | 29718390 | |
dc.identifier | 85055426974 | |
dc.identifier | 000441792600017 | |
dc.identifier.citation | Svensson , 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/jiy242 | en |
dc.identifier.issn | 0022-1899 | |
dc.identifier.other | ORCID: /0000-0001-6537-7712/work/45366208 | |
dc.identifier.uri | https://hdl.handle.net/10023/17599 | |
dc.description | This 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.abstract | Background 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.format.extent | 3059496 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Infectious Diseases | en |
dc.subject | Pharmacodynamics | en |
dc.subject | Tuberculosis | en |
dc.subject | Pharmacokinetics | en |
dc.subject | Patients | en |
dc.subject | Time to positivity | en |
dc.subject | Early bactericidal effect | en |
dc.subject | Mycobacterium tuberculosis | en |
dc.subject | RA0421 Public health. Hygiene. Preventive Medicine | en |
dc.subject | RM Therapeutics. Pharmacology | en |
dc.subject | NDAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | RA0421 | en |
dc.subject.lcc | RM | en |
dc.title | Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations | en |
dc.type | Journal article | en |
dc.contributor.sponsor | European Commission | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.contributor.institution | University of St Andrews. Infection and Global Health Division | en |
dc.contributor.institution | University of St Andrews. Global Health Implementation Group | en |
dc.contributor.institution | University of St Andrews. Gillespie Group | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. Infection Group | en |
dc.identifier.doi | 10.1093/infdis/jiy242 | |
dc.description.status | Peer reviewed | en |
dc.date.embargoedUntil | 2019-04-28 | |
dc.identifier.grantnumber | en |
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