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MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues.

Silvia Maria Lavezzi1,2, Enrica Mezzalana1,3, Stefano Zamuner4

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This study evaluates minimal physiologically-based pharmacokinetic (mPBPK) and target-mediated drug disposition (TMDD) model integration. Simplifications in TMDD dynamics can impact model accuracy and identifiability, requiring careful consideration during experimental design.

Keywords:
IdentifiabilityMinimal physiologically-based pharmacokineticsMonoclonal antibodiesStudy designTarget mediated drug disposition

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Area of Science:

  • Pharmacokinetics and Pharmacodynamics
  • Mathematical Modeling
  • Drug Development

Background:

  • Minimal physiologically-based pharmacokinetic (mPBPK) models are crucial for predicting drug behavior.
  • Integrating mPBPK with target-mediated drug disposition (TMDD) models enhances predictive power, especially in tissue compartments.
  • Assessing model identifiability is vital for reliable predictions and experimental validation.

Purpose of the Study:

  • To evaluate model identifiability of integrated mPBPK-TMDD models in the tissue compartment.
  • To investigate the impact of different quasi-steady-state (QSS) approximations on model identifiability.
  • To provide a framework for assessing mathematical model properties before experimental application.

Main Methods:

  • Simulations were conducted using a reference mPBPK-TMDD model without simplifications.
  • Three QSS approximations (antibody-target complex, free target, free antibody) were explored.
  • Local sensitivity analysis and a priori/a posteriori identifiability assessments were performed under various experimental scenarios.

Main Results:

  • Approximation of antibody-target complex concentrations did not affect model outcomes.
  • Approximations of free target or free antibody concentrations led to deviations in drug and/or target profiles.
  • Identifiability issues were detected, particularly for models with multiple QSS approximations, necessitating specific sampling strategies and dose ranges.

Conclusions:

  • The choice of QSS approximations in integrated mPBPK-TMDD models significantly impacts their identifiability.
  • Target concentration data and sampling during the terminal pharmacokinetic phase are crucial for maintaining model identifiability.
  • Careful consideration of model complexity and experimental design is necessary to address identifiability challenges in mPBPK-TMDD applications.