Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications

Benjamin Guiastrennec, Geetha Ramachandran, Mats O. Karlsson, A. K.Hemanth Kumar, Perumal Kannabiran Bhavani, N. Poorana Gangadevi, Soumya Swaminathan, Amita Gupta, Kelly E. Dooley, Radojka M. Savic

Research output: Contribution to journalArticle

Abstract

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 (4–7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable). Model-based simulation of optimized (Punfavorable ≤ 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.

Original languageEnglish (US)
Pages (from-to)733-741
Number of pages9
JournalClinical pharmacology and therapeutics
Volume104
Issue number4
DOIs
StatePublished - Oct 2018

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Guiastrennec, B., Ramachandran, G., Karlsson, M. O., Kumar, A. K. H., Bhavani, P. K., Gangadevi, N. P., Swaminathan, S., Gupta, A., Dooley, K. E., & Savic, R. M. (2018). Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications. Clinical pharmacology and therapeutics, 104(4), 733-741. https://doi.org/10.1002/cpt.987