Affiliation:
1. Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, New Delhi;
2. ICMR-National Institute for Research in Tuberculosis, Chennai;
3. National Institute for Tuberculosis and Respiratory Diseases, New Delhi;
4. Government Thiruvatteeswarar Hospital of Thoracic Medicine, Chennai;
5. Group of TB Hospitals, Mumbai; and
6. B.J.Medical College and Hospital, Ahmedabad, India.
Abstract
Background:
Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events.
Methods:
A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events.
Results:
The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (Cmin) and time–concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median Cmin and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters.
Conclusions:
Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure–response relationship.
Funder
United States Agency for International Development
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Pharmacology (medical),Pharmacology
Reference20 articles.
1. Treatment of highly drug-resistant pulmonary tuberculosis;Conradie;N Engl J Med,2020
2. Bedaquiline, delamanid, linezolid and clofazimine for treatment of pre-extensively drug-resistant tuberculosis;Padmapriyadarsini;Clin Infect Dis,2022
3. Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial;Goodall;Lancet,2022
4. Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis;Zuur;Expert Opin Drug Metab Toxicol,2016
5. Clinical standards for the dosing and management of TB drugs;Alffenaar;Int J Tuberc Lung Dis,2022