Opportunities and Challenges for PBPK Modelling in Specific Populations: Considerations for Paediatrics, Pregnancy, Lactation, Ethnic Differences, and Organ Impairment.

Physiologically based pharmacokinetic (PBPK) modelling represents a key component of model-informed drug development (MIDD), providing a mechanistic framework to predict drug disposition in populations often underrepresented in clinical research. By integrating drug-specific properties with detailed physiological and biochemical parameters, PBPK models bridge knowledge gaps created by ethical, logistical, and safety constraints, enabling evidence-based dosing and supporting more inclusive pharmacotherapy.This chapter examines the application of PBPK modelling across populations in which physiological, pathological, or genetic factors substantially influence pharmacokinetics - namely, paediatrics, pregnant and lactating women, individuals with hepatic or renal impairment, and populations defined by ethnic or pharmacogenomic variability. In each case, PBPK models allow extrapolation from healthy adult data to predict exposure, optimise dosing, and inform study design or regulatory decision-making.Despite their growing impact, challenges remain due to limited physiological data, complex physiological variability, and ethical hurdles. Nevertheless, advances in quantitative systems data, computational techniques, and model qualification frameworks are steadily improving predictive performance. Regulatory agencies increasingly endorse PBPK modelling within MIDD pathways for dose selection, study optimisation, and labelling in specific populations.Looking forward, integration with real-world data, artificial intelligence, and digital health technologies, alongside harmonised regulatory standards, will further enhance model credibility and clinical utility. These developments will reinforce the role of PBPK modelling in ensuring safe, effective, and equitable drug therapy across diverse and physiologically distinct populations.