Drug Effect of Clofazimine on Persisters Explains an Unexpected Increase in Bacterial Load in Patients
Date
2020-04
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Abstract
ABSTRACT Antituberculosis (anti-TB) drug development is dependent on informative
trials to secure the development of new antibiotics and combination regimens.
Clofazimine (CLO) and pyrazinamide (PZA) are important components of recommended
standard multidrug treatments of TB. Paradoxically, in a phase IIa trial aiming
to define the early bactericidal activity (EBA) of CLO and PZA monotherapy over
the first 14 days of treatment, no significant drug effect was demonstrated for the
two drugs using traditional statistical analysis. Using a model-based analysis, we
characterized the statistically significant exposure-response relationships for both
drugs that could explain the original findings of an increase in the numbers of CFU
with CLO treatment and no effect with PZA. Sensitive analyses are crucial for exploring
drug effects in early clinical trials to make the right decisions for advancement
to further development. We propose that this quantitative semimechanistic approach
provides a rational framework for analyzing phase IIa EBA studies and can
accelerate anti-TB drug development.
Description
CITATION: Faraj A, Svensson RJ, Diacon AH,Simonsson USH. 2020. Drug effect of clofazimine on persisters explains an
unexpected increase in bacterial load in patients. Antimicrob Agents Chemother 64:e01905-19. https://doi.or/10.1128/AAC
.01905-19.
Keywords
Mycobacterium tuberculosis, drug development, pharmacodynamics, pharmacokinetics
Citation
doi.org/10.1128/AAC.01905-19.