Advancing Pediatric Dose Scaling: Strategies, Modeling Approaches, and Clinical Applications.

Background/Objectives: Selecting appropriate doses for pediatric patients remains one of the most complex challenges in drug development because developmental changes in physiology, metabolism, organ function, and pharmacodynamics substantially influence drug exposure and response. This review summarizes current evidence-based approaches to pediatric dose selection across the developmental continuum and evaluates contemporary model-informed strategies for individualized dosing. Methods: A narrative review of the literature was conducted focusing on pediatric dose-scaling methodologies, developmental pharmacology, physiologically based pharmacokinetic (PBPK) modeling, population pharmacokinetic (PopPK) approaches, exposure-response analysis, therapeutic drug monitoring, and regulatory extrapolation frameworks. Special populations and clinical scenarios relevant to pediatric dose optimization were also evaluated. Results: Simple body weight-based scaling from adult doses inadequately accounts for developmental changes in drug disposition and response. Allometric scaling combined with maturation functions provides improved dose prediction in neonates and infants, while PBPK and PopPK modeling support mechanistic and data-driven dose optimization across pediatric age groups. Fat-free-mass (FFM)-based scaling is preferred over total body weight for many drugs in children with obesity. Additional considerations including obesity, biologics, formulation and excipient safety, pharmacogenomics, critical illness, therapeutic hypothermia, extracorporeal support, therapeutic drug monitoring, and drug-drug interactions substantially influence pediatric dosing strategies. Regulatory frameworks including ICH E11A increasingly support model-informed pediatric extrapolation and precision dosing approaches. Conclusions: Pediatric dose selection has evolved from empirical weight-based dosing toward integrated model-informed strategies incorporating developmental physiology, pharmacometrics, and regulatory science. Allometry, maturation functions, FFM-based scaling, PBPK, PopPK, and therapeutic drug monitoring provide complementary tools for rational pediatric dose optimization, although drug- and pathway-specific validation remains essential, particularly in neonates and critically ill children.