Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis

Abstract

Background: Pharmacokinetic data are needed for newly implemented anti-Tuberculosis drugs to help optimize their use. Objectives: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-Tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis. Methods: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored. Results: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine. Conclusions: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.