Integrating Real-World Data and Pharmacometrics to Bridge Evidence Gaps in Special Populations: A State-of-the-Art...

Background/Objectives: Special populations, including pediatric, geriatric, and organ-impaired patients, are consistently underrepresented in randomized controlled trials (RCTs), resulting in limited evidence for safe and effective dosing. Off-label use is common, and variability in drug exposure and response increases the risk of adverse drug reactions (ADRs). This review aims to examine how integrating pharmacometrics (PMX) with real-world data (RWD) can address evidence gaps by supporting dose optimization, population expansion, and safety evaluation in these vulnerable groups. Methods: A narrative literature review was conducted using PubMed, Embase, and Web of Science (January 2000-November 2025). Using Boolean combinations of PMX and RWD-related search terms, approximately 200-300 records were identified across the three databases; approximately 30 full-text articles were reviewed, and representative case studies were selected based on population diversity, methodological variation, and regulatory or clinical impact. Results: RWD-PMX integration has been applied across three domains: (i) dosing optimization through therapeutic drug monitoring (TDM)-informed PopPK modeling and model external validation in pediatric and neonatal populations; (ii) population expansion supporting dose extrapolation and regulatory decision-making for unapproved groups; and (iii) safety evaluation enabling identification of exposure-toxicity risk factors in vulnerable cohorts. Conclusions: Integrating PMX with RWD provides a practical and mechanistically grounded framework for evaluating dosing, treatment eligibility, and safety in populations insufficiently represented in clinical trials. Accumulating evidence indicates that RWD-PMX methodologies can complement traditional clinical research and inform regulatory decision-making. Continued refinement of data quality standards, validation practices, and guidance frameworks will be essential for broader adoption.