Endpoint Exposure-Response Analyses in the Presence of Concurrent Dose Modification During Clinical Trials

Area of Science:

• Pharmacometrics
• Drug Development
• Clinical Pharmacology

Background:

• Exposure-response (E-R) analyses are vital for drug dose selection.
• Conventional E-R methods often ignore dose modifications (DMs) caused by adverse events (AEs), potentially biasing results.
• Understanding the impact of AE-driven DMs on E-R relationships is critical for accurate drug assessment.

Purpose of the Study:

• To develop a framework for quantifying the impact of AE-driven DMs on E-R relationships.
• To explore strategies for improving the accuracy of E-R analyses in the presence of DMs.
• To evaluate E-R relationships considering both planned and actual dose exposures.

Main Methods:

• Utilized duvelisib, a drug with frequent DMs, as a case study.
• Compared three E-R scenarios: ground truth, conventional (planned exposure), and DM-adjusted (actual exposure).
• Assessed the influence of AE onset timing and DMs on E-R relationship accuracy.

Main Results:

• Conventional E-R analyses significantly deviated from ground truth with frequent DMs, especially for delayed AEs.
• Early-onset AEs and subsequent DMs distorted E-R relationships for later AEs.
• DM-adjusted E-R analyses improved accuracy for late AEs but risked overcorrection for early AEs.

Conclusions:

• Incorporating AE timing and DMs into E-R analyses is essential for robust drug development.
• Accurate interpretation of E-R relationships requires accounting for real-world clinical events like DMs.
• This framework enhances the reliability of dose selection in drugs with frequent AE-driven dose modifications.