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 Elise 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 (4-7kg) 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)
JournalClinical Pharmacology and Therapeutics
DOIs
StateAccepted/In press - Jan 1 2018

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Rifampin
India
HIV
Guidelines
Pediatrics
Pharmaceutical Preparations
Tuberculosis
Pyrazinamide
Isoniazid
Therapeutics
Treatment Failure
Coinfection
HIV Infections
Pharmacokinetics
Body Weight
Weights and Measures
Population

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Guiastrennec, B., Ramachandran, G., Karlsson, M. O., Kumar, A. K. H., Bhavani, P. K., Gangadevi, N. P., ... Savic, R. M. (Accepted/In press). Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.987

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India : Recommendations for Dose Modifications. / Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O.; Kumar, A. K.Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N. Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly Elise; Savic, Radojka M.

In: Clinical Pharmacology and Therapeutics, 01.01.2018.

Research output: Contribution to journalArticle

Guiastrennec, Benjamin ; Ramachandran, Geetha ; Karlsson, Mats O. ; Kumar, A. K.Hemanth ; Bhavani, Perumal Kannabiran ; Gangadevi, N. Poorana ; Swaminathan, Soumya ; Gupta, Amita ; Dooley, Kelly Elise ; Savic, Radojka M. / Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India : Recommendations for Dose Modifications. In: Clinical Pharmacology and Therapeutics. 2018.
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