Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 104, Issue 4, Pages 733-741Publisher
WILEY
DOI: 10.1002/cpt.987
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Funding
- National Institute for Child Health and Human Development [R01HD074944]
- Clinical and Translational Science Institute [8 KL2 TR000143-07]
- Swedish Research Council Formas [521-2011-3442]
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This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P-unfavorable). Model-based simulation of optimized (P-unfavorable 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.
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