PI-061 - CLOFAZIMINE PHARMACOKINETICS FOR MULTIDRUG-RESISTANT TB: IMPLICATION OF NOVEL COMBINATION REGIMENS.

B. Ngara¹, B. Solans², E. Yang³, M. Gouillou⁴, D. Vargas Vasquez⁵, E. Śanchez Garavito⁶, F. Garcia⁷, K. Khazhidinov^8,9, A. Magzumova¹⁰, H. Nguyen¹¹, H. Phan¹², S. Wasserman¹³, U. Khan¹⁴, A. Aftab¹⁵, S. Mpinda¹⁶, P. Van Brantegem³, S. Mohale¹⁶, D. Holtzman¹⁶, L. Wiesner¹⁷, F. Varaine¹⁸, R. Savic^3,19, H. McIlleron¹⁷, G. Velásquez^19,20; ¹University of California San Francisco, San Francisco, California, USA, ²UCSF, San Francisco, California, USA, ³University of California, San Francisco, San Francisco, CA, United States, ⁴Epicentre, Paris, France, ⁵Pneumology Service, Hospital Nacional Hipólito Unanue, Lima, Peru, ⁶Pneumology Service, Hospital Nacional Sergio Bernales, Lima, Peru, ⁷Partners In Health/Socios En Salud Sucursal Peru, Lima, Peru, ⁸Partners In Health-Kazahkstan, Almaty, Kazakhstan, ⁹Site Management Organization Medical Education and Research Alliance, Almaty, Kazakhstan, ¹⁰Partners In Health-Kazahkstan, Almaty, Kazahkstan, ¹¹National Lung Hospital, Hanoi, Vietnam, ¹²VNTP-UCSF Research Collaboration Unit; Center for Promotion of Advancement of Society, Hanoi, Vietnam, ¹³Institute for Infection and Immunity, City St George's, University of London, London, United Kingdom, ¹⁴Interactive Research and Development(IRD), Dubai, United Arab Emirates, ¹⁵Interactive Research and Development(IRD), Karachi, Pakistan, ¹⁶Partners In Health-Lesotho, Maseru, Lesotho, ¹⁷Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, ¹⁸MSF-France, Paris, France, ¹⁹UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States, ²⁰Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, United States.

Background: Multidrug-resistant (MDR) tuberculosis (TB) remains a major threat to the treatment of TB worldwide. Clofazimine (CFZ) is currently listed as a “Group B” drug and recommended as a second-choice agent for the treatment of MDR-TB by WHO.

Methods: CFZ pharmacokinetic (PK) data was obtained from adults and adolescents (>15 years) who were enrolled in the PandrTB PKPD sub-study (NCT03827811) of the endTB (NCT02754765) and endTB-Q (NCT03896685) Phase 3 tuberculosis therapeutic trials. The PK data was analyzed using a non-linear mixed effect model in NONMEM v7.5.1 to quantify exposure to clofazimine and explore the impact of co-administration with other anti-TB drugs and other relevant covariates on variability in CFZ PK model parameters and area under curve (AUC).

Results: A total of 100 participants’ PK data enrolled from 7 locations was included in the analysis. The mean age was 37 years and 32% were female. About 18% had diabetes mellitus, 75%, and 68% had delamanid and clofazimine co-administration. CFZ PK data were best described using a 2-compartmental model structure with first-order absorption. When clofazimine was administered with delamanid, there was a 28% reduction and a 25% increase in clofazimine clearance and AUC, respectively. Diabetes was associated with a 40% reduction and a 38% increase in clofazimine clearance and AUC, respectively. When clofazimine was administered with pyrazinamide, there was a 67% and a 6% reduction in clofazimine peripheral volume of distribution and AUC, respectively.

Conclusion: At the 5% significance level, both the co-administration with delamanid and diabetes mellitus are associated with increased clofazimine exposure.