How long will treatment guidelines for TB continue to overlook variability in drug exposure?

Abstract

Despite wide clinical acceptance, the use of weight-banded dosing regimens for the treatment of TB in adults has been defined on an empirical basis. The potential impact of known covariate factors on exposure to different drugs has not been taken into account. To evaluate the effect of demographic factors on the exposure to standard of care drugs after weight-banded dosing, as currently recommended by TB treatment guidelines. In addition, we aim to identify alternative dosing regimens that ensure comparable systemic exposure across the overall patient population. Clinical trial simulations were performed to assess the differences in systemic exposure in a cohort of virtual patients. Secondary pharmacokinetic parameters were used to evaluate the adequacy of each regimen along with the percentage of patients achieving predefined thresholds. Our results show that patients weighing less than 40 kg are underexposed relative to patients with higher body weight. The opposite trend was observed following a crude weight band-based dosing regimen with 50 kg as the cut-off point. Simulations indicate that a fixed-dose regimen based on three (<40 kg), four (40-70 kg) or five (>70 kg) tablets of 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide and 275 mg ethambutol reduces variability in exposure, increasing the overall probability of favourable long-term outcome across the population. These findings suggest the need to revisit current guidelines for the dose of standard of care drugs for TB treatment in adults. The proposed fixed-dose regimen should be considered in future clinical trials.