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

• Published in: British journal of clinical pharmacology 2019-03, Vol.85 (3), p.644-654
• Main Authors: Aruldhas, Blessed Winston, Hoglund, Richard M., Ranjalkar, Jaya, Tarning, Joel, Mathew, Sumith K., Verghese, Valsan Philip, Bose, Anuradha, Mathew, Binu Susan
• Format: Article
• Language: English
• Subjects: Adolescent; Age Factors; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacokinetics; Body Weight; Child; Child, Preschool; dose adequacy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; India; Infant; isoniazid; Isoniazid - administration & dosage; Isoniazid - pharmacokinetics; Male; Metabolic Clearance Rate; Models, Biological; Original; paediatric; population pharmacokinetic; rifampicin; Rifampin - administration & dosage; Rifampin - pharmacokinetics; tuberculosis; Tuberculosis - blood; Tuberculosis - drug therapy
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13846

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.