Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16years of age: Supportive evidence for the implementation of revised WHO dosing recommendations

摘要

Objectives The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. Methods Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8h after intake of TB drugs by 30TB patients aged 1-15years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. Results 25 patients (83%) had an isoniazid Cmax below 3mg/l and 23 patients (77%) had a rifampicin Cmax below 8mg/l. One patient (3%) had a pyrazinamide Cmax below 20mg/l. The low number of patients on ethambutol (n=5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P0.01). Conclusion We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.