A Patient-Centered Approach for Drug-Drug Interaction (DDI) Assessment: Integrating Nested Clinical DDI Studies to Verify Translatability of Healthy Volunteer DDI Data, Minimize Stand-Alone Trials, and Enrich Drug Labeling.

The pharmaceutical industry often adopts a stepwise approach, assuming that drug-drug interaction (DDI) results obtained in healthy volunteers (HVs) are translatable to patients. This strategy typically begins with evaluating DDIs in HVs using probe drugs, followed by assessing interactions with potential concomitant medications, often supported by physiologically based pharmacokinetic modeling. Findings from HV studies are subsequently extrapolated to patient populations to inform drug labeling. However, this approach has limitations: (i) DDI results obtained from HV studies may not always be able be to translate to patients due to disease-related physiological changes; (ii) ethical and cost concerns arise when administering investigational drugs to HVs in clinical setting; and (iii) physiologically based pharmacokinetic modeling may be insufficient in predicting DDIs across diverse clinical scenarios. One way to address these challenges is the nested DDI study, where DDI assessments are perceptively embedded within phase II or III clinical trials. [1]. We reviewed US Food and Drugs Administration approvals over recent decades and found that nested/patient-based DDI evaluations were considered sufficient by Food and Drug Administration to support DDI labeling for 86% of new chemical entities and 92% of biologics. This design helps verify HV-to-patient translatability, reduces HV exposure, lowers operational costs, and strengthens labeling. Importantly, nested DDI studies can confirm known interactions, uncover new DDIs, and address gaps in physiologically based pharmacokinetic predictions. In conclusion, prospectively integrating nested DDI studies into development programs supports efficient risk assessment, enhances patient safety, and improves clinical relevance. Regulators and drug developers should consider nested designs as a standard component of DDI evaluation.