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

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.

• Authors: 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
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 104 Issue 4 Pg. 733-741 (10 2018) ISSN: 1532-6535 [Electronic] United States
• PMID: 29247506 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Antitubercular Agents
• Pyrazinamide
• Isoniazid
• Rifampin

Topics

• Adolescent
• Age Factors
• Antitubercular Agents (administration & dosage, adverse effects, pharmacokinetics)
• Body Weight
• Child
• Child, Preschool
• Coinfection
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Dosage Calculations
• Drug Monitoring
• Drug Therapy, Combination
• Female
• HIV Infections (diagnosis, epidemiology)
• Humans
• India (epidemiology)
• Infant
• Isoniazid (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Models, Biological
• Pyrazinamide (administration & dosage, adverse effects, pharmacokinetics)
• Rifampin (administration & dosage, adverse effects, pharmacokinetics)
• Time Factors
• Treatment Outcome
• Tuberculosis (blood, diagnosis, drug therapy, epidemiology)