PII-060 - CHALLENGES IN PREDICTING PEDIATRIC DRUG EXPOSURE WITH ALLOMETRIC SCALING: IMPLICATIONS FOR OPTIMIZING PEDIATRIC TRIAL DESIGNS

X. Zhou¹, M. Shin¹, T. Chung¹, R. Miyakawa², R. Savic^3,4; ¹University of California San Francisco, San Francisco, CA, United States, ²Weill Cornell Medicine, Department of Pediatrics, Weill Cornell Medicine, Department of Pediatrics, NY, US, ³University of California, San Francisco, San Francisco, CA, United States, ⁴UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States.

Background: In pediatric clinical trial designs, selecting the initial dose is crucial to ensuring equivalent drug exposure across children of varying ages, weights, and nutritional statuses, since ethical constraints limit multiple dosing evaluations. The most common practice for suggesting an opening dose is application of allometry. Similarly, majority of pediatric clinical trial designs are not adaptive and do not allow for interim analysis and dose refinement. This study focuses on the field of global health, where WHO frequently updates dosing guidelines, with tuberculosis (TB) as a case study. Our goal is to assess the predictive performance of allometric scaling from adult population pharmacokinetic (popPK) models and provide insights for optimizing pediatric trial designs and dosing strategies.

Methods: A PubMed search identified 12 adult popPK models and 4 pediatric models focusing on second-line TB drugs (bedaquiline, linezolid, moxifloxacin, and delamanid) for which WHO has most recently updated or published dosing recommendations for childhood multi-drug resistant TB. 50% of the adult models already incorporated body weight as a covariate. For models that did not, allometric scaling (clearance: 0.75, volume: 1) was applied. Pediatric clearance was extrapolated from adult models, and the largest studies for each drug were used to assess exposure based on practical pediatric dosing regimens.

Results: 67% of the adult popPK models with allometric scaling failed to predict the clearance (± 20%) observed in pediatric models (Figure 1). For linezolid, whose toxicity remains a concern despite its efficacy in children, adult models significantly underestimated pediatric drug exposure by 49%, resulting in higher-than-expected drug levels in actual pediatric populations at the doses used in pediatric trials.

Conclusion: Based on our findings, allometric scaling of adult popPK models may have limitations in accurately predicting pediatric clearance and drug exposure for second-line TB drugs. This is likely because the complexity and variability in pediatric patients extend beyond body weight alone, potentially impacting opening dose selection and trial design. Our findings exemplified need for adaptive clinical trial designs that enable interim analysis and doses refinement, so clinical safety can be achieved at the doses of interest.