PT-025 - EVALUATION OF PYRAZINAMIDE PHARMACOKINETICS IN ADOLESCENTS AND ADULTS TO INFORM TUBERCULOSIS DOSING RECOMMENDATIONS.

M. Yoon¹, R. Savic^1,2; ¹University of California, San Francisco, San Francisco, CA, USA, ²UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, USA.

Background: Adolescents can be grouped with either children or adults in clinical trials, leading to potential dosing issues as pediatric models and dosing recommendations may differ from those for adults. This study evaluates whether adult population pharmacokinetic (popPK) models for tuberculosis (TB) treatment are suitable for adolescents, focusing on pyrazinamide, one of the main TB drugs. We hypothesize that adolescent PK profiles closely resemble those of adults, supporting the use of adult PK models for adolescent dosing.

Methods: We used PK data from the S31 trial (NCT02410772) with participants aged 13-81 years with TB (n=2,272). The popPK model (Xu et al., 2024), featuring a 1-compartment disposition and 1 absorption transit compartment with 1st-order absorption and elimination that was generated for total participants in this trial was reassessed by stratifying the data into adults (19+ years) and adolescents (13-18 years). Differences in demographics and disease status between these groups were evaluated. Individual estimates for clearance and volume of distribution were determined using NONMEM software. The impact of weight and age on clearance was also assessed, and model performance was evaluated using goodness-of-fit and visual predictive checks.

Results: Demographics and disease status matched well between adults (n=2,155) and adolescents (n=117). Pyrazinamide PK data showed significant overlap between the groups. The original model (CL=3.53 L/hr, V= 33.4L) fit both groups well, with similar estimates (adult CL= 3.54 L/hr, V= 33.4L; adolescent CL= 3.35 L/hr, V= 34.1L). Weight and age had weak negative correlations with clearance, suggesting they may not need to be considered for dosing pyrazinamide. These findings support using adult doses of pyrazinamide for adolescents 12 years and older.

Conclusion: Adult-based TB dosing appears appropriate for adolescents based on PK similarities observed in this preliminary analysis, particularly with pyrazinamide, where neither age nor weight was a significant covariate. Future steps include comparisons with pediatric data (under 12 years) to determine if pediatric models should also be considered. Eventually, we will extend this evaluation to all other drugs for TB. These findings thus far support optimizing TB drug regimens for adolescents using adult models.