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

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 .

Clinical Pharmacology & Therapeutics; 2018; 104(4): 733-741.   

Abstract: 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 pro?les 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 identi?ed 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 (Pun favorable). Model-based simulation of optimized (Pun favorable5%) rifampin once-daily doses were suggested pretreatment 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.

Study Highlights: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

India recently updated its national tuberculosis treatment guidelines and is now moving toward a once-daily dosing regimen. The optimal doses of ?rst-line drugs for all children, in India or elsewhere, has not been ?rmly established.

WHAT QUESTION DID THIS STUDY ADDRESS?

What are the subpopulations at risk of unfavorable treatment outcomes (therapy failure, death), and what modi?cations can be made to the new once-daily Indian pediatric tuberculosis treatment guidelines to reduce this risk in these subgroups?

WHAT THIS STUDY ADDS TO OUR KNOWLEDGE

Low rifampin exposures were linked to an increased probability of unfavorable treatment outcome. Rifampin exposure was the lowest in children with low body weight or HIV coinfection.

HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE

Clinical practice in India is evolving and this work provides vital information to inform dosing guidelines of the future. More speci?cally, our simulations suggest that higher antituberculosis drug dose levels in Indian children, especially those with low body weight or HIV coinfection, can potentially prevent treatment failure or death.

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