Clinical impact of plasma concentrations of first-line antituberculosis drugs

BACKGROUND: The clinical significance of low antituberculosis (anti-TB) drug concentrations has not been fully elucidated. OBJECTIVES: To investigate the clinical consequences of first-line drug concentrations in adult patients with drug-susceptible pulmonary TB in South Africa (SA). METHOD: We conducted a pharmacokinetic study nested within the control arm of the Improving Treatment Success (IMPRESS) trial (NCT 02114684) in Durban, SA. During the first 2 months of treatment, participants received weight-based dosing of first-line anti-TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol), and had plasma drug concentrations measured at 2 and 6 hours after drug administration during the 8th week of treatment. Intermediate (8 weeks), end-of-treatment (6 months) and follow-up TB outcomes were assessed using World Health Organization criteria. RESULTS: We measured plasma drug concentrations on available samples in 43 participants. Peak drug concentrations were below the therapeutic range in 39/43 (90.7%) for rifampicin, 32/43 (74.4%) for isoniazid, 27/42 (64.3%) for pyrazinamide and 5/41 (12.2%) for ethambutol. At the end of the intensive phase of treatment (week 8), 20.9% (n=9/43) of participants remained culture positive. We did not find a relationship between the concentrations of first-line drugs and treatment outcomes at week 8. All participants were cured at the end of treatment, and there were no relapses during the 12-month follow-up period. CONCLUSION: Treatment outcomes were favourable despite low drug concentrations as defined by current reference thresholds.