Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis

Abstract

Objective: To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).

Design: Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.

Setting: Hasan Sadikin Hospital, Bandung, Indonesia.

Patients: Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.

Interventions: Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.

Main outcome measures: Plasma exposures during the daily dosing interval (AUC_0-24), peak plasma concentrations (C_max) and CSF concentrations.

Results: Among 20 eligible patients, geometric mean AUC_0-24 of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC_0-24 and C_max of all drugs. All patients had suboptimal rifampicin AUC_0-24 for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC_0-24 of isoniazid, rifampicin and pyrazinamide along with C_max of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).

Conclusion: Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.

Keywords: microbiology; pharmacology; therapeutics.

Figure 1

Pharmacokinetic profiles (drug concentration vs time curves) of isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) in children and adolescents treated for tuberculous meningitis on days 2 and 10 of treatment. (A) INH in plasma; (B) RIF in plasma; (C) PZA in plasma; (D) INH in cerebrospinal fluid (CSF); (E) RIF in CSF; (F) PZA in CSF.

Figure 2

Pharmacokinetic profiles of isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) on day 10 of tuberculous meningitis treatment in children and adolescents who developed antituberculosis drug-induced liver-injury (DILI, n=3*) and those without DILI (n=9). (A) INH plasma concentration vs time curve; (B) RIF plasma concentration vs time curve; (C) PZA plasma concentration vs time curve; (D) INH area under the concentration–time curve during the dosing interval (AUC_0–24); (E) RIF AUC_0–24; (F) PZA AUC_0–24. Box plots represent medians with IQRs; lower and upper whiskers represent first and fourth quartiles, respectively. *Of four patients with DILI, one who developed DILI on day 7 of treatment did not have INH, RIF and PZA concentrations measured on day 10 because the drugs had been temporarily stopped due to DILI.