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Pharmacodynamic Models of Indirect Effects and Irreversible Inactivation with Turnover: Applicability to

Angelia F Wang1, Vivaswath S Ayyar1

  • 1Clinical Pharmacology & Pharmacometrics, Janssen Research and Development, Spring House, PA, USA.

Journal of Pharmaceutical Sciences
|October 26, 2023
PubMed

Insights

Indirect response (IDR) and turnover with inactivation (TI) models mathematically converge, unifying delayed drug effect modeling. This research clarifies their properties and applicability for gene-silencing and protein-degrading agents.

Area of Science:

  • Pharmacodynamics
  • Pharmacokinetics
  • Systems Biology

Background:

  • Indirect response (IDR) and turnover with inactivation (TI) are key mechanism-based pharmacodynamic models for delayed drug effects.
  • Classical IDR-IV and TI models exhibit distinct response-time profiles based on dose and time to peak response.
  • Understanding their mathematical relationship is crucial for accurate drug effect modeling.

Purpose of the Study:

  • To demonstrate the mathematical convergence of IDR-IV and TI models.
  • To explore the influence of pharmacologic effect terms on model behavior.
  • To propose a generalized dynamic model for mRNA and protein turnover.

Main Methods:

  • Mathematical analysis of IDR-IV and TI models with linear and nonlinear pharmacologic effect terms.
  • Model-fitting to pharmacokinetic-pharmacodynamic (PK-PD) data from PROTACs and siRNA agents.
  • Investigation of PK and PD parameter influence on response time.

Main Results:

  • IDR-IV and TI models demonstrate mathematical convergence under identical conditions.
  • The time of peak response in IDR-IV models is sensitive to PK/PD parameters and effect type.
  • The generalized model effectively describes mRNA and protein turnover dynamics.
  • Model-fitting successfully applied to PROTACs and siRNA PK-PD data.

Conclusions:

  • IDR-IV and TI models are mathematically linked, offering a unified framework for delayed drug effects.
  • The study clarifies model properties, convergence, and expected responses for targeted gene-silencing and protein-degrading agents.
  • Well-designed in vivo studies are essential for robust PK-PD model selection and parameter estimation.
Keywords:
Indirect pharmacodynamic responseIrreversible inactivationPharmacokinetic/pharmacodynamic (PK/PD) modelingProteolysis-targeting chimera (PROTAC)Small interfering RNA (siRNA)Turnover

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