Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Abstract

Aims Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. Methods Data were collected from 41 children, aged 2–16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed‐effects model. Results Isoniazid pharmacokinetics were described by a one‐compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one‐compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed‐dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed‐dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg–1, was found to provide adequate drug exposure in most children. Conclusions The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose–effect relationship of higher doses of rifampicin.

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

“…Simulations of optimal doses demonstrated that 10 mg/kg/day of isoniazid, which is the currently recommended WHO dose, was adequate to maintain steady-state plasma and CSF exposures above the EC 50 with PTA >90% in both fast and slow acetylators. Similar results were reported in a previous study by Aruldhas et al, who studied pulmonary and lymph node TB in Indian children aged 2 to 16 years ( 19 ). However, a study by Zvada et al showed that the dose of 10 mg/kg/day resulted in inadequate exposure in intermediate and fast acetylators ( 31 ).…”

“…Due to those findings, current pediatric dose recommendations from the WHO in 2014 have been increased, i.e., isoniazid 10 mg/kg, rifampin 15 mg/kg, pyrazinamide 35 mg/kg, and ethambutol 20 mg/kg daily ( 14 ). Still, this increased dosing has been shown to fail to achieve therapeutic drug concentrations in certain pediatric studies ( 18 – 20 ).…”

Disseminated Bacillus-Calmette-Guérin Infections and Primary Immunodeficiency Disorders in Singapore: A Single Center 15-Year Retrospective Review

“…(Chan et al, 2017) Singaporean Chinese were found to be predominantly fast acetylators (75%), while Singaporean Indians were primarily slow acetylators (62.5%). (Aruldhas et al, 2019) At the current World Health Organisation (WHO) recommended pediatric doses, the simulated target attainment of the therapeutic peak INH concentrations (Cmax > 3 mg ml À1 ), and amount of exposure (AUC 0-24 > 10.5 mg x h ml À1 ) are close to !90% in both fast and slow acetylators. (Aruldhas et al, 2019) This suggests that the low-level INH resistance may not correspond to clinical resistance, as sufficient drug concentrations are still attained in vivo, and hence, high-dose INH is not required.…”

“…(Rieder and Van Deun, 2017;Katiyar et al, 2008;Jacobson et al, 2011;Xu et al, 2017) However, at the current World Health Organisation (WHO) recommended doses for pediatrics at 10 -15 mg/kg/day, isoniazid concentrations to overcome the phenotype of decreased drug susceptibility may already be readily obtained in-vivo. (Aruldhas et al, 2019;Rangari et al, 2015) INH metabolism is dependent on the genotype of the N-acetyltransferase (NAT) enzyme, explaining the large variability in its clearance. Fast acetylators are generally at risk of drug underexposure, and a Singapore-based study found that close to 64% of the cohort were fast acetylators, with variation in ethnicity.…”

Four months of rifampicin monotherapy for latent tuberculosis infection in children

“…However, when rifampicin 35-40 mg/kg was administered to children weighing 6-30 kg, 74.2% had a Cmax greater than 8 μg/mL. 27) In a pediatric study, children with low blood levels of rifampicin were more likely to have…”