Clofazimine pharmacokinetics in novel rifampicin-resistant tuberculosis regimens: an analysis of the endTB and endTB-Q trials
Year: 2026
Type: preprint
Abstract: Introduction Rifampicin-resistant tuberculosis poses a significant threat worldwide. Clofazimine is considered important for the construction of effective individualized multidrug regimens to treat rifampicin-resistant tuberculosis. Our goal was to characterize clofazimine pharmacokinetics in novel combination treatment regimens and to identify participant characteristics associated with variations in drug exposure. Methods Clofazimine pharmacokinetic data were obtained from adults and adolescents enrolled in the PandrTB pharmacokinetic sub-study of the endTB and endTB-Q Phase 3 randomized controlled therapeutic trials for rifampicin-resistant tuberculosis. Plasma concentrations were analyzed using nonlinear mixed-effects modeling to quantify clofazimine exposure and explore the impact of relevant covariates. Results 100 participants from six countries with high burdens of rifampicin-resistant tuberculosis contributed pharmacokinetic data. Their median age was 34 years, 32% were female, 18% were living with diabetes mellitus, and 18% were living with HIV. Clofazimine plasma concentration values were best described by a 2-compartment pharmacokinetic model with first-order absorption. Co-administration with delamanid and HIV co-infection resulted in a 37% increase and 20% decrease in clofazimine bioavailability, respectively. Diabetes was associated with a 43% decrease in clofazimine clearance. Clofazimine remained in the body for a median of 2.5 years (95th percentile: 0.5 to 8) following 9 months of treatment. Conclusion Co-administration with delamanid, diabetes mellitus, and HIV were associated with variation in clofazimine exposure. We estimated that clofazimine remained present in the body for longer than two years in over half of participants following 9 months of treatment. Follow-up studies are recommended to confirm these associations before adjusting clofazimine dose or clinical care decisions.
Source: medRxiv
Authors: Bernard Ngara, Belén P Solans, Eunsol Yang, Pieter Van Brantegem, Lorenzo Guglielmetti, Francis Varaine, Maelenn Gouillou, Carole D. Mitnick, Allison N. LaHood, Michael L. Rich, Kwonjune J. Seung, Lubbe Wiesner, Loren Hans, Rina Swart, Amanzhan Abubakirov, Kanat Khazhidinov, Anel Belgozhanova, Stephane Mpinda, Sesomo Mohale, David Holtzman, Dante Vargas Vásquez, Fanny García Velarde, Sergio Mucching-Toscano, Annum Aftab, Mahnoor S. Arshad, Azka Ashraf, Luong V. Dinh, Hanh T.T. Nguyen, Ha T.T. Phan, Sean Wasserman, Nelisiwe Ntuli, Radojka M. Savic, Helen McIlleron, Gustavo E. Velásquez, PandrTB Study Group
Institutions: University of California, San Francisco, Ospedale Sacro Cuore Don Calabria, Médecins Sans Frontières, Epicentre, Brigham and Women's Hospital, Partners In Health, Harvard University, University of Cape Town, University of the Western Cape, Interactive Research and Development, Indus Hospital, Hanoi Lung Hospital, Bệnh viện Phổi Trung ương, Center for Promotion of Advancement of Society, Queen Mary University of London, Wellcome Centre for Infectious Diseases Research in Africa, Blizard Institute, Institute of Infectious Disease and Molecular Medicine, Médecins Sans Frontières, UCSF Institute for Global Health Sciences
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1575283533, G2969723535, G3661324716, G4166928756, Pharmacometrics to advance novel regimens for drug-resistant tuberculosis (PandrTB), Pharmacometrics to advance novel regimens for drug-resistant tuberculosis (PandrTB), G7647017494, G7785852513, G9000129761, Harvard University Center for AIDS Research
OpenAlex ID: W7213759516