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 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 (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 development of future pediatric tuberculosis treatment guidelines.

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Dosing guidelines for antituberculosis drugs typically advocate a uniform milligram per kilogram of body weight (mg/kg) dose, and the drugs are typically dosed by weight band to achieve a narrow mg/kg range using the available formulations [40,41]. A consistent finding of pharmacokinetic studies in adults and children dosed in this way is that lower weight patients have lower drug exposures [5,10,13,18,33,37,[42][43][44]. This can be attributed to the nonlinear relationship between clearance and size whereby smaller people need higher maintenance doses per kilogram of body weight [45].…”

“…Studies in patients with drug-susceptible tuberculosis (DS-TB) on a standard regimen of rifampin and isoniazid for 6 months with pyrazinamide and ethambutol for the first 2 months, suggest that such variability is clinically important. Specifically, patients with relatively low systemic exposures to rifampin and pyrazinamide have worse treatment outcomes [4,6], while rifampin, isoniazid and pyrazinamide exposures are related to the decline in bacterial load in the sputum during the weeks following initiation of treatment [6,8,[14][15][16][17][18]. For ethambutol and isoniazid, as well as second-line drugs for drug-resistant tuberculosis (DR-TB), such as linezolid, cycloserine, moxifloxacin, aminoglycosides, and capreomycin toxicity, are dose-related.…”

Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study

“…20,22,[25][26][27] Optimized FDC formulations were explored based on the individualized doses, but drug doses and dose ratios varied by pharmacokinetic model and isoniazid metabolizing capacity. Our work along with others 16,28 suggests that higher anti-tuberculosis doses and new FDC formulations are needed to ensure optimal outcomes. However, it remains unclear from current pediatric pharmacologic data whether a single global FDC formulation can meet the needs of all children.…”

“…Drug exposures were estimated for rifampicin, isoniazid, and pyrazinamide using two published and peer-reviewed population pharmacokinetic models (appendix, page 9). 16,17 Individual child pharmacokinetic parameters were sampled from the established population distribution, defined with median values and between-child variability. Pharmacokinetic profiles were simulated in R using Monte Carlo for each drug and dosing method assuming once-daily oral administration with full adherence to represent the most promising scenario (i.e., treatment completion).…”

“…17 For rifampicin, a child-specific target defined from an exposure-response model was used, where the relationship between rifampicin AUCss over one week (AUCwk) is related to the probability of unfavorable event (Punf), defined as death or treatment failure, aligning with the fact that rifampicin is the most important drug in the regimen. 16 Using this model, we defined the rifampicin exposure target as AUCwk > 222 mg*h/L, which results in a Punf < 5%, and predicted the Punf for each child.…”