Pediatric Extrapolation in Neuropsychiatric Drug Development: Leveraging Pharmacokinetic and Pharmacodynamic...

Pediatric extrapolation enables the application of adult efficacy data to pediatric populations when sufficient similarity is established in disease pathophysiology, pharmacologic response, and drug exposure. When these conditions are met, extrapolation can reduce or eliminate the need for dedicated pediatric efficacy trials, facilitating more efficient pediatric drug development. In this paper, we examined US Food and Drug Administration (FDA) pediatric drug approvals in neurology, analgesia, and psychiatry from 2014 to 2025 that utilized exposure matching to support extrapolation approaches. We identified 33 unique drug products that successfully implemented pharmacokinetic-based exposure matching strategies across neuropsychiatric indications. Population pharmacokinetic modeling emerged as the predominant strategy for pediatric dose optimization, incorporating developmental considerations such as allometric scaling and enzyme maturation functions. FDA General Advice Letters proved instrumental in facilitating adoption of complete pediatric extrapolation approaches, demonstrating the critical role of regulatory guidance in expediting pediatric drug development. Case examples spanned broad age ranges, from mechanistically informed neonatal applications utilizing enzyme maturation modeling (risdiplam) to adolescent populations where adult dosing regimens proved adequate (brexanolone, nipocalimab). Additionally, pharmacodynamic biomarkers were pivotal in pediatric extrapolation of eculizumab and nipocalimab efficacy for the treatment of generalized myasthenia gravis, highlighting promising future directions for the field. These cases demonstrate how achieving comparable pharmacokinetics and, when necessary, pharmacodynamics profiles between adult and pediatric populations can support efficient regulatory approval without dedicated pediatric efficacy studies. The regulatory pathways established for select neuropsychiatric indications provide a compelling framework for expanding extrapolation approaches to other therapeutic areas.