PI-089 - POPULATION PHARMACOKINETICS OF PYRAZINAMIDE FOR PATIENTS WITH MULTIDRUG RESISTANT TUBERCULOSIS
Wednesday, May 28, 2025
5:00 PM - 6:30 PM East Coast USA Time
Z. Li1, E. Yang2, P. Van Brantegem2, M. Gouillou3, D. Vargas Vasquez4, E. SÌanchez Garavito5, F. Garcia6, K. Khazhidinov7,8, A. Magzumova9, H. Nguyen10, H. Phan11, S. Wasserman12, U. Khan13, A. Aftab14, S. Mpinda15, S. Mohale15, D. Holtzman15, L. Wiesner16, F. Varaine17, R. Savic2,18, H. McIlleron16, G. Velásquez18,19; 1UCSF, San Francisco, CA, US, 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, 17MSF-France, Paris, France, 18UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States, 19Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, United States.
Postdoc Fellow University of California, San Francisco San Francisco, California, United States
Background: Pyrazinamide (PZA) is recommended by the World Health Organization to treat multidrug-resistant tuberculosis (MDR-TB) in certain regimens. However, its pharmacokinetics (PK) in this population are seldom analyzed. This study aims to analyze the PK of PZA in patients with MDR-TB and identify the influence of covariates on PK. Methods: A total of 560 PZA concentrations from 91 participants were collected from the PandrTB sub-study of the endTB (NCT02754765) and endTB-Q (NCT03896685) trials randomized controlled trials. Blood samples were collected at pre-dose and at 1.5, 3, 4.5, 6, 8, and 10-12 h after drug administration. Plasma concentrations of PZA were determined by LC–MS/MS method. Nonlinear mixed-effects modeling was applied to interpret the PK data. The population PK model of PZA in drug-susceptible TB patients from previous literature was used to simulate the area under the concentration-time curve (AUC) and was compared with the simulated results from this study. Results: A one-compartment model with delayed absorption best fits the PK of PZA. Inter-individual variability was added to clearance (CL), volume of distribution (V), and absorption delayed time (Alag). Inter-occasion variability was added to CL. Body weight with allometric scaling on both CL and V highly improved the model performance. Fasting can increase the absorption time by 0.357 h. Females showed a 14.1% lower V than males. In addition, the CL of PZA decreased with treatment duration, with a decrease of 11.8% at 9 months of treatment. MDR-TB participants showed about 70% higher PZA exposure than that reported for those drug-susceptible TB. Conclusion: The developed population PK model adequately described the PK of PZA in MDR-TB trial participants. We observed higher PZA exposures in persons with MDR-TB compared with what has been reported for drug-susceptible TB. Sex, body weight, food intake, and treatment duration were identified as significant covariates, which can be used for PZA dose optimization for the treatment of MDR-TB.