PII-094 - UNRAVELING MOXIFLOXACIN'S BEHAVIOR IN NEXT-GENERATION TB REGIMENS.

A. Bustion¹, E. Yang², P. Van Brantegem², M. Gouillou³, D. Vargas Vasquez⁴, E. Śanchez Garavito⁵, F. Garcia⁶, K. Khazhidinov^7,8, A. Magzumova⁹, H. Nguyen¹⁰, H. Phan¹¹, S. Wasserman¹², U. Khan¹³, A. Aftab¹⁴, S. Mpinda¹⁵, S. Mohale¹⁵, D. Holtzman¹⁵, M. Mazanhanga¹⁶, L. Wiesner¹⁷, F. Varaine¹⁸, R. Savic^2,19, H. McIlleron¹⁷, G. Velásquez^19,20; ¹University of California San Francisco, San Francisco, CA, USA, ²University of California, San Francisco, San Francisco, CA, United States, ³Epicentre, Paris, France, ⁴Pneumology Service, Hospital Nacional Hipólito Unanue, Lima, Peru, ⁵Pneumology Service, Hospital Nacional Sergio Bernales, Lima, Peru, ⁶Partners In Health/Socios En Salud Sucursal Peru, Lima, Peru, ⁷Partners In Health-Kazahkstan, Almaty, Kazakhstan, ⁸Site Management Organization Medical Education and Research Alliance, Almaty, Kazakhstan, ⁹Partners In Health-Kazahkstan, Almaty, Kazahkstan, ¹⁰National Lung Hospital, Hanoi, Vietnam, ¹¹VNTP-UCSF Research Collaboration Unit; Center for Promotion of Advancement of Society, Hanoi, Vietnam, ¹²Institute for Infection and Immunity, City St George's, University of London, London, United Kingdom, ¹³Interactive Research and Development(IRD), Dubai, United Arab Emirates, ¹⁴Interactive Research and Development(IRD), Karachi, Pakistan, ¹⁵Partners In Health-Lesotho, Maseru, Lesotho, ¹⁶Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, Cape Town, South Africa, 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: Moxifloxacin (MXF) is critical for multidrug-resistant tuberculosis (MDR-TB) and rifampicin-resistant TB (RR-TB) regimens. MXF may prolong the QT interval, particularly when co-administered with other QT-prolonging drugs, and clofazimine co-administration may alter MXF bioavailability. Despite its broad use, therefore, MXF interactions with companion drugs are inadequately understood. This study aimed to characterize MXF in two novel regimens and explore the impact of drug-drug interactions and patient-specific factors on its pharmacokinetics (PK).

Methods: We analyzed two MXF-containing regimens in the PandrTB (NCT03827811) observational sub-study of endTB (NCT02754765), a Phase 3 randomized controlled trial. N=38 participants with pulmonary TB received 400mg QD of oral MXF for nine months, with 288 plasma concentration observations. Data was analyzed using non-linear mixed effects modeling (NONMEM 7.5.0), guided by objective function value, goodness-of-fit, and visual predictive check plots. Clinical covariates were tested for effects on PK parameters using Stepwise Covariate Model-building (scmplus).

Results: A one-compartment model with linear absorption and elimination best described the data. Allometric scaling was applied to clearance and volume of distribution. Inter-individual variability was implemented on clearance, and inter-occasion variability on bioavailability. The final model aligned with previous MXF PK models, and uniquely, estimated the unbound fraction. Two covariates were statistically significant and included in the final model: serum albumin (negatively correlated with clearance; p=0.002), and sex (lower volume of distribution in females; p=0.00002). Clofazimine co-administration had no significant effect.

Conclusion: This population PK model for MXF in two novel anti-TB regimens revealed significant associations between MXF PK and participant-specific factors (sex, serum albumin). Contrary to previous reports, clofazimine co-administration did not significantly affect MXF PK. These findings have important implications for optimizing MXF dosing in MDR-TB and RR-TB regimens, potentially improving participant outcomes and reducing adverse effects.