Suboptimal anti-tuberculosis drug concentrations and outcomes in small and HIV coinfected children in India: recommendations for dose modifications

Post Date: 
2017-12-01
Publication: 
Clinical Pharmacology and Therapeutics
Clinical Site(s): 
Summary: 

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.

Citation: 
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
Collaborators: 
  • Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
  • National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
  • University of California San Francisco, San Francisco, CA, USA.