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Suboptimal anti-tuberculosis drug concentrations and outcomes in small and HIV coinfected children in India: recommendations for dose modifications
Clinical Pharmacology and Therapeutics
This work aimed to evaluate the once-daily anti-tuberculosis 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 (4–7 kg) and/or human immunodeficiency virus (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 development of future pediatric tuberculosis treatment guidelines.
Guiastrennec B, Ramachandran G, Karlsson MO, Kumar AKH, Bhavani PK, Gangadevi NP, Swaminathan S, Gupta A, Dooley KE, Savic RM. Suboptimal anti-tuberculosis drug concentrations and outcomes in small and HIV coinfected children in India: recommendations for dose modifications. Clin Pharmacol Ther. 2017 Dec 16. doi: 10.1002/cpt.987. [Epub ahead of print] PMID: 29247506