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Modeling functional tolerance observed in a Phase II population (PD Series – Part 1, 2025)

Presented by Drs. Johan Gabrielsson and Bernd Wendt - 21 May 2025

Updated this week

Webinar Overview

This analysis evaluates the impact of pharmacodynamic tolerance and rebound effects on the clinical development of a first-in-class metabolic drug.

Core Findings

  • Adaptive Response (Tolerance): Data from Phase 1 and 2 trials show that the body’s physiological systems adapt to the drug, reducing its effectiveness over time.

  • The Rebound Risk: Abrupt discontinuation or missed doses trigger a "rebound," where biomarker levels fall significantly below the patient's original pathological baseline. This poses a specific safety risk for older patients.

  • Age as a Variable: The study confirmed that age significantly alters drug potency and the body’s ability to synthesize the target biomarker, requiring age-adjusted dosing.

Strategic Recommendations

  • Model-Based Design: A "Feedback Moderator Model" has been validated to accurately predict these fluctuations. This model should be used to guide Phase 3 dosing.

  • Dosing Consistency: Clinical protocols must emphasize strict adherence to dosing schedules to prevent the dangerous "trough" associated with the rebound effect.

  • Phase 3 Optimization: By utilizing the feedback model, the Phase 3 study can employ sparse sampling, reducing patient burden while maintaining high data integrity for regulatory submission.

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