118: Evaluation of Drug-Drug Interaction in Nested Patient Studies

Statement of Purpose, Innovation or Hypothesis: Usage of population-based approach has gained acceptance by the US Food and Drug Administration (FDA) in assessing drug-drug interactions (DDIs). Compared to dedicated DDI studies conducted in healthy volunteers, population-based approach can detect clinical effects in target patient populations. Recently, the FDA released clinical DDI guidelines advocating the use of prospective nested studies to evaluate DDI in patient populations alongside population pharmacokinetic (popPK), which can yield informative and sometimes conclusive analyses. This research aims to evaluate FDA-approved drugs through nested DDI studies using popPK or trough concentration analysis (TCA) and then establish comprehensive guidelines for their application.

Description of Methods & Materials: A comprehensive key word search of the terms “popPK”, “TCA” and “drug interaction” was conducted in PubMed® to identify both FDA-approved new chemical entities (NCEs) and new biologic entities (NBEs) since 1965. Key factors evaluated in nested DDI studies included drug-interaction profiles, therapeutic areas (TAs), pharmacokinetic (PK) profiles, co-medications, patient sample size, and covariates. These factors were obtained from the Clinical Pharmacology reviews in FDA database and published literature in PubMed®. The label claim examination was based on the results of the sponsors’ analyses and the agency’s comments regarding the nested DDI studies.

Data & Results: Fifty-six FDA-approved drugs (NCEs = 30, NBEs = 26) were evaluated. Among 30 NCEs, 4 drugs were reported using TCA, and the FDA accepted all submissions for label claims. Of the 26 NCEs using popPK approach, 22 (86.7%) drugs’ label claims were accepted by the FDA. The reasons for failure in label claims included incorrect assumption for simulation, inadequate popPK-based evaluation, and limited sample size. Among the FDA-approved drug labels, the median total subjects and interacting drug sample sizes were 457 (range: 78 – 1771) and 68 (range: 7 – 874) respectively. Fourteen drugs reported enzyme-mediated DDI, of which 10 assessed CYP3A4 liability. Fifteen NCEs were evaluated with co-medications relevant to TAs for DDI, 2 of them also relevant to mechanism. The popPK approach assessed PK profiles of 26 NBEs as either the victim, perpetrator, or both. The median sample sizes assessed with FDA-approved drug labels were 447 (range: 60 – 1093) and 218 (range: 45 – 548) for total subjects and interacting drug sample sizes, respectively. All 26 NBEs were evaluated with comedications relevant to TAs for DDI. Out of the 26 drugs, 9 (35%) showed changes in their PK profiles, but these changes were not clinically relevant. The FDA accepted all evaluations as valid evidence for label claims.

Interpretation, Conclusion or Significance: Among NCEs, the popPK approach is commonly used to evaluate DDIs in patient populations compared to TCA approach. NBE submissions use popPK approach to confirm the absence of DDI liability complying with FDA guidelines. While popPK analysis has its limitations, this research finding demonstrates that nested DDI studies are a valid and FDA-approved method for assessing DDI potentials for label claims and help in avoiding the expense of dedicated DDI studies in the target patient population. Moreover, concomitant medication DDIs within relevant TAs in the target population potentially offer valuable insights into the interaction between the disease and DDIs.

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Additional Information/Authors: C. F. Chan, Y. S. Scaringella, F. Huang