期刊
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
卷 10, 期 5, 页码 366-379出版社
WILEY
DOI: 10.1111/cts.12472
关键词
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资金
- National Institutes of Health [R01AI111992]
- Critical Path to TB Drug Regimens initiative through the Bill & Melinda Gates Foundation [OPP1031105]
- National Institutes of Health
- U.S. Food and Drug Administration
- Bill & Melinda Gates Foundation
- Global Alliance for TB Drug Development
- Clinical Pharmacology Postdoctoral Fellowship at JHU
- Ruth L. Kirschstein National Research Service Award T32 National Institutes of Health [5T32GM007546]
- Bill and Melinda Gates Foundation [OPP1031105] Funding Source: Bill and Melinda Gates Foundation
Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72-87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.
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