Rifampicin pharmacokinetics in children under the Revised National Tuberculosis Control Programme, India, 2009

Abstract

Low serum concentrations of RMP were attained in children under the RNTCP 2009 weight band system. Peak RMP levels appear to be lower and the single dose elimination half-life shorter in children than in adults. To optimise treatment outcomes, revisions in RMP dose in children should take into consideration age-related differences in pharmacokinetics.

Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis

“…Table 1 shows the breakdown between favorable and unfavorable outcomes and loss to follow-up, as reported by the individual studies. Reported risk factors for unfavorable outcomes included lower drug exposures, including for RIF [ 23 , 26 , 29 ], INH [ 19 , 23 ], and PZA [ 24 ], as well as lower weight for age [ 19 ] or severe malnutrition [ 36 ], poor social circumstances [ 15 ], and severity of infection [ 33 ].…”

“… Percentage of reported favorable outcomes per study, with the risk factors identified in the listed publications [ 14 , 15 , 19 , 20 , 23 , 24 , 26 , 29 , 30 , 33–35 ]. Colors indicate whether children in the study received World Health Organization (WHO)–recommended doses of first-line antituberculosis agents or doses based on Revised National Tuberculosis Control Program guidelines.…”

“…Younger age was associated with lower exposures in 1 study [ 29 ], and CWHIV were reported to have lower exposures in another study [ 14 ] ( Table 1 ). Higher RIF doses were associated with statistically significant increased PK levels in 4 studies [ 16 , 21 , 26 , 27 ] ( Table 1 ). Within-study dose comparison in 2 studies showed higher C max and AUC at 0–12 hours with doses >10 mg/kg [ 21 , 26 ], confirmed by additional studies reporting an increase of 0.12 µg·h/mL in AUC 0–last (AUC at 0 to the last measured time) ( P = .03) and 0.2 (95% confidence interval [CI], .1–.4) μg/mL in C max for each additional milligram per kilogram ( P = .005) [ 16 , 27 ].…”

Pharmacology of Mycobacterial Drugs in Children

“…Studies conducted in India report mixed findings (0-58.7% attaining the recommended targets); however, the studies offer a clear indication that the likelihood of achieving adequate concentrations increases with increasing age. 16,[42][43][44] Importantly, adult studies indicate that a substantial fraction of adults similarly fail to attain the recommended pharmacodynamics target for rifampin, highlighting the large degree of inter-individual variability in rifampin PK and the degree of uncertainty in the recommendation that concentrations at 2 hours exceed 8 µg/mL. 22 It is also important to recognize that many of the pediatric studies described above report favorable clinical outcomes in children despite failure to meet pharmacodynamics targets.…”

“…22 It is also important to recognize that many of the pediatric studies described above report favorable clinical outcomes in children despite failure to meet pharmacodynamics targets. 20,42 Nonetheless, pharmacokinetic modeling coupled with accumulated practical experience is leading experts to recommend pediatric doses of at least 15 to 20 mg/kg and upward of 30 mg/kg while treating CNS infection. [45][46][47]…”