Challenges in Extrapolating Healthy Volunteer Pharmacokinetics to Oncology Populations: Advocating for a Holistic Perspective.

Phase I clinical pharmacology (CP) studies in healthy volunteers (HVs) are conducted to assess factors influencing drug pharmacokinetic (PK) properties and guide potential dose adjustments or restrictions for specific subpopulations within the target patient population. However, for oncology drugs, direct extrapolation from HV data may not always yield accurate outcomes. This review examines three published examples-ribociclib, ceritinib, and midostaurin-where substantial changes in drug exposure observed in CP studies conducted in HVs (or non-cancer subjects) did not align with the more modest effects seen in patient trials. While HV CP studies are crucial for detecting factors that alter drug exposure, their findings may not always translate to the oncology patient population. The underlying reasons are likely multifaceted but can at least be attributed to differences in study populations and study designs. To address this potential discrepancy, the relevance of intrinsic and extrinsic factors identified in HV studies should be validated in patient trials by assessing their impact on drug PK, safety, and efficacy. These examples highlight the importance of a holistic approach that integrates data from both HV and patient studies. Such a framework ensures more informed decisions about the safe and effective use of oncology drugs in the real-world settings.