Rethinking pharmacokinetics in preterm and term neonates and infants: sex as a critical biological variable

INTRODUCTION: Neonates and infants are not 'small adults.' Rapid developmental changes in body size, composition, organ function, and enzyme and transporter expression profoundly influence pharmacokinetics (PK). In the last decades, sex emerged as an underrecognized variable affecting growth, metabolism, and drug disposition even in early life. AREA COVERED: This review critically evaluates evidence on the ontogeny of absorption, distribution, metabolism, and excretion (ADME) in neonates and infants (0-24 months). Key factors influencing PK include gestational and postnatal age, feeding, gut microbiota, enzyme and transporter maturation, and drug formulation. Evidence highlights sex-dependent differences in physiology, enzyme activity, drug absorption, distribution, metabolism, and elimination, which can affect drug efficacy and toxicity. Breast milk composition, formula type, and early-life microbiota can interact with sex to modulate drug disposition.Challenges include limited clinical data, widespread off-label prescribing, ethical constraints in pediatric trials and insufficient integration of sex in study design. EXPERT OPINION: The recognition of age-dependent sex differences in ADME, as well as formulation effects, is essential for optimizing drug safety and efficacy in early life. Physiologically based PK modeling, therapeutic drug monitoring, and sex-stratified clinical studies should be systematically implemented to guide personalized dosing strategies and improve outcomes in neonates and infants.