Physiologically Based Pharmacokinetic Modeling of Drug Disposition in Undernourished Adolescents

Undernutrition alters physiological processes relevant to drug disposition, yet pharmacokinetic data in undernourished pediatric populations remain sparse due to ethical and practical constraints. Physiologically based pharmacokinetic (PBPK) modeling provides a mechanistic framework to evaluate how disease-related physiological changes may influence drug exposure in such vulnerable groups. The aim of this study was to develop and apply PBPK models for adolescents with anorexia nervosa (AN) and non-edematous malnutrition (MN), and to evaluate the impact of nutritional status on the pharmacokinetics of drugs with diverse physicochemical properties and elimination pathways. Custom adolescent virtual populations representing AN and MN were constructed in the Simcyp® simulator using literature-derived physiological scalars describing changes in body composition, organ size, blood flow, and enzyme and transporter activity. A healthy adolescent population served as the reference. Five probe compounds – caffeine, atorvastatin, midazolam, metformin, and zidovudine – were selected to represent a range of metabolic pathways, including CYP-mediated metabolism, renal transporter-mediated clearance, and high lipophilicity. All compounds were simulated following single-dose oral administration, and pharmacokinetic outputs including area under the concentration-time curve (AUC), maximum concentration (Cmax), apparent oral clearance (Dose/AUC), volume of distribution at steady state (Vss), and plasma concentration-time profiles were analyzed. Overall, simulations showed increased systemic exposure and reduced clearance in AN and MN compared with healthy controls, with compound-specific effects dependent on the dominant absorption, distribution, metabolism, and excretion (ADME) pathway and most pronounced changes observed in the MN populations. Considering several factors influencing the simulations – most notably the limited availability of pediatric malnutrition-specific physiological data – the findings of this study should be interpreted with caution. Further development of pediatric population files informed by richer clinical datasets, including organ-level physiological and biochemical measurements, would strengthen future PBPK applications and enable more refined predictions of drug disposition in undernourished children and adolescents.