Related Experiment Video
Updated: Jun 19, 2026
07:31
Realistic Membrane Modeling Using Complex Lipid Mixtures in Simulation Studies
Published on: September 1, 2023
Physiologically-based PK/PD modelling of therapeutic macromolecules
Peter Thygesen1, Panos Macheras, Achiel Van Peer
1Exploratory ADME, Novo Nordisk A/S, Måløv, Denmark. ptt@novonordisk.com
Pharmaceutical Research
|October 23, 2009
Summary
Physiologically-based pharmacokinetic (PBPK) modeling is feasible for therapeutic proteins, offering in silico predictions for drug development. This approach aids in understanding complex drug disposition, including target-mediated distribution and lymphatic transport.
Area of Science:
- Pharmacology
- Biotechnology
- Computational Biology
Background:
- Therapeutic proteins present unique challenges in pharmacokinetic (PK) and pharmacodynamic (PD) studies due to their size and properties.
- Physiologically-based pharmacokinetic (PBPK) modeling is a valuable tool for in silico prediction of drug properties.
Purpose of the Study:
- To discuss the feasibility and desirability of applying PBPK modeling to macromolecules, specifically therapeutic proteins.
- To explore advanced PBPK modeling strategies for complex drug disposition.
Main Methods:
- Review of classical PBPK modeling using cyclosporine A as a case study, incorporating membrane transport and protein binding.
- Discussion of complex PBPK modeling approaches for macromolecules, including permeability-limited and target-mediated distribution.
Main Results:
- General agreement that PBPK modeling is both feasible and desirable for therapeutic proteins.
- Consideration of the lymphatic system's role in extravascular administration and target-mediated drug disposition (TMDD) as key modeling features.
Conclusions:
- PBPK modeling is a viable and beneficial approach for predicting the behavior of therapeutic proteins.
- Mechanistic PK/PD models are crucial for incorporating adverse events and toxicity into drug development assessments.
Related Concept Videos
01:27Pharmacodynamic Models: Overview
Pharmacodynamic (PD) responses describe the interaction between a drug and its biological target, culminating in a physiological effect. These responses can be classified into different types: continuous variables, such as blood glucose levels; categorical outcomes, like survival rates; and time-to-event metrics, such as disease progression. Understanding and modeling PD responses are critical for optimizing drug efficacy and safety.PD models describe the relationship between drug concentration...
01:24Pharmacokinetic–Pharmacodynamic Relationship: Problems
The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...
01:14Pharmacokinetic–Pharmacodynamic Relationship: Model Components
Pharmacokinetic-pharmacodynamic (PK–PD) modeling is essential in drug development and clinical pharmacology. It provides a quantitative framework to predict drug behavior and response over time. This approach integrates pharmacokinetics (PK), which describes the drug's absorption, distribution, metabolism, and excretion, with pharmacodynamics (PD), which characterizes the drug’s biological effects and mechanisms of action.The disposition kinetics of a drug determine its plasma...
01:13Physiological Pharmacokinetic Models: Assumption with Protein Binding
Physiological models with protein binding in pharmacokinetics offer a sophisticated approach to understanding drug disposition. These models consider drug-protein interactions, enabling them to effectively predict drug concentrations in different organs and tissues. This precision aids in accurate drug dosing, providing a significant advantage over conventional models. A key process within these models is equilibration, which ensures that drug concentrations achieve a steady state within the...
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion, mediated...
A recent model describes pravastatin's hepatobiliary excretion, mediated...
01:26Pharmacokinetic Models: Comparison and Selection Criterion
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.