Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis

ABSTRACT

Introduction

Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children.

Areas covered

This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities.

Expert opinion

New data consistently show low rifampicin exposures across all pediatric populations with 10–20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.

KEYWORDS:

• Rifampicin
• pharmacokinetics
• children
• dosing
• formulations
• malnutrition
• HIV
• tuberculosis

Article highlights

• Emerging pharmacokinetic data of rifampicin in children at WHO-recommended doses (10-20 mg/kg daily) show lower drug exposures (C_max and AUC) than in adult populations and poor target attainment.

• Several pediatric rifampicin population pharmacokinetic models exist; however, differences in model parameterization and variability, in part due to the data from which they were built, result in varied optimal dosing predictions that need reconciliation.

• Important scientific questions remain about rifampicin pharmacokinetics and optimal dosing in pediatric populations with high TB morbitidy and mortality, including children with HIV, TB meningitis, and malnutrition and under 5 years of age.

• Rifampicin doses higher than currently recommended are now being evaluated in clinical trials for special populations (e.g. TB meningitis) or treatment shortening.

• Current pediatric formulations of rifampicin were developed for optimal implementation of current weight band dosing recommendations that have since shown to result in suboptimal exposure. Re-evaluation of rifampicin formulations for children is needed.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was not funded.