# Effect of Interindividual Variability in Metabolic Clearance and Relative Bioavailability on Rifampicin Exposure in Tuberculosis Patients with and without HIV Co-Infection: Does Formulation Quality Matter?

## TL;DR

This study examines how factors like HIV co-infection and drug formulation affect the body's response to rifampicin in tuberculosis patients.

## Contribution

The study identifies body weight and formulation quality as key factors affecting rifampicin exposure, independent of HIV co-infection.

## Key findings

- HIV co-infection does not alter plasma exposure to rifampicin.
- Relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard FDC regimen.
- Participants weighing less than 50 kg have lower RIF plasma exposure compared to those over 50 kg.

## Abstract

The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV− group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation.