期刊
JOURNAL OF INFECTIOUS DISEASES
卷 218, 期 6, 页码 991-999出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiy242
关键词
Pharmacodynamics; tuberculosis; pharmacokinetics; patients; time to positivity; early bactericidal activity; models; bactericidal effect; Mycobacterium tuberculosis
资金
- Swedish Research Council [521-2011-3442]
- Innovative Medicines Initiative Joint Undertaking [115337]
- European Union
- European Federation of Pharmaceutical Industries and Associations
- European and Developing Countries Clinical Trials Partnership [IP.2007.32011.011, IP.2007.32011.012, IP.2007.32011.013]
- Netherlands-African Partnership for Capacity Development and Clinical Interventions Against Poverty-Related Diseases
- Bill and Melinda Gates Foundation
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.
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