Therapeutic Window Determination

Case Study

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Therapeutic window determination leading to NoGo decision

Goal: Provide requested support for Phase 2a dose selection  

Available information

  • Targeted indication is non-lethal with different requirements on benefit-risk than in oncology
  • PK, biomarker PD data from an oncology FIP study in different indication
  • DLTs seen in FIP study
  • Competitor information
    • Targeting same mechanism of action
    • Published In-vitro concentration / response biomarker
    • Published mean PK profiles at different dose levels
    • Information at which dose-level clinically relevant efficacy is observed (conference slide)
    • In-silico calculation of partition coefficients for competitor
  • Information on tissue distribution


  • Original question: What would be suitable Phase 2a doses?


  • Development of population PK model based on oncology FIP study data
  • Development of population PK/PD model linking dose/concentration to biomarker inhibition
  • Leverage competitor information to inform relationship biomarker inhibition / clinically relevant effect
  • PK/PD modeling for safety readout (continuous marker)
  • Simulation based integration of all information for communication purposes

Benefit for the Client

  • Population PK analysis revealed a very long halflife and huge PK variability. Due to FIP study design this was not realized before
  • Characterization of required exposure thresholds for efficacy and concentration range of expected DLTs revealed the non-presence of a therapeutic window for this compound in the considered indication
  • Project team went for an early NoGo decision
  • Decision to wait for backup compound with far more favorable physchem properties

R based PK/PD modeling workflow

We helped a client leverage the power of open-source modeling tools for internal modeling and simulation tasks

Reproducible Analyses

Computation without Borders and Reproducible Analyses: IQ Desktop

Phase IIb Design

Confident transition to full development