PII-019 - POPULATION PHARMACOKINETICS OF DELAMANID AND ITS METABOLITE DM-6705 IN MULTIDRUG-RESISTANT TUBERCULOSIS PATIENTS RECEIVING NOVEL SHORT-COURSE ORAL REGIMENS IN THE ENDTB AND ENDTB-Q TRIALS

E. Yang¹, P. Van Brantegem¹, M. Gouillou², D. Vargas Vasquez³, E. Śanchez Garavito⁴, F. Garcia⁵, K. Khazhidinov^6,7, A. Magzumova⁸, H. Nguyen⁹, H. Phan¹⁰, S. Wasserman¹¹, U. Khan¹², A. Aftab¹³, S. Mpinda¹⁴, S. Mohale¹⁴, D. Holtzman¹⁴, L. Wiesner¹⁵, F. Varaine¹⁶, R. Savic^1,17, H. McIlleron¹⁵, G. Velásquez^17,18; ¹University of California, San Francisco, San Francisco, CA, United States, ²Epicentre, Paris, France, ³Pneumology Service, Hospital Nacional Hipólito Unanue, Lima, Peru, ⁴Pneumology Service, Hospital Nacional Sergio Bernales, Lima, Peru, ⁵Partners In Health/Socios En Salud Sucursal Peru, Lima, Peru, ⁶Partners In Health-Kazahkstan, Almaty, Kazakhstan, ⁷Site Management Organization Medical Education and Research Alliance, Almaty, Kazakhstan, ⁸Partners In Health-Kazahkstan, Almaty, Kazahkstan, ⁹National Lung Hospital, Hanoi, Vietnam, ¹⁰VNTP-UCSF Research Collaboration Unit; Center for Promotion of Advancement of Society, Hanoi, Vietnam, ¹¹Institute for Infection and Immunity, City St George's, University of London, London, United Kingdom, ¹²Interactive Research and Development(IRD), Dubai, United Arab Emirates, ¹³Interactive Research and Development(IRD), Karachi, Pakistan, ¹⁴Partners In Health-Lesotho, Maseru, Lesotho, ¹⁵Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, ¹⁶MSF-France, Paris, France, ¹⁷UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States, ¹⁸Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, United States.

Background: Delamanid is a WHO-recommended nitroimidazole for the treatment of multidrug-resistant tuberculosis (MDR-TB). The Phase 3 endTB trial recently demonstrated the noninferiority of three novel all-oral, shortened regimens, including one combining delamanid with bedaquiline, linezolid, levofloxacin, and pyrazinamide (BDLLZ), compared to standard MDR-TB therapies. Here, we performed a population pharmacokinetic analysis of delamanid and its metabolite DM-6705 in MDR-TB patients, leveraging data from the endTB (NCT02754765) and endTB-Q (NCT03896685) trials in the PandrTB pharmacokinetics/pharmacodynamics sub-study (NCT03827811).

Methods: We analyzed plasma concentration-time data of delamanid (595 observations) and DM-6705 (696 observations) from 99 MDR-TB patients who received one of four novel delamanid-containing regimens in the endTB or endTB-Q trials. Delamanid was administered at a flat dose of 100 mg twice daily with food. We assessed the impact of various potentially influential factors, such as the coadministration of companion drugs, on the pharmacokinetics of delamanid and DM-6705. The analysis was performed using nonlinear mixed-effects modeling approach with NONMEM v.7.5.1.

Results: Delamanid pharmacokinetics was best described by a two-compartment model with sequential zero- and first-order absorption and linear elimination, while DM-6705 pharmacokinetics was well described by a one-compartment model with delamanid clearance as input and linear elimination. Concomitant administration of other anti-TB drugs – such as bedaquiline, clofazimine, linezolid, levofloxacin, moxifloxacin, and pyrazinamide – did not affect the pharmacokinetics of either delamanid or DM-6705. Neither the timing of food intake nor the fat content in meals had a significant influence on delamanid absorption.

Conclusion: The pharmacokinetics of delamanid and DM-6705 were successfully characterized by a joint pharmacokinetic model, providing a worthwhile rationale for the future use of delamanid, particularly in combination with other anti-TB drugs within promising shorter oral regimens for MDR-TB. Our model will be further utilized to explore the relationships between delamanid exposure and efficacy and safety outcomes in the trials.