Related Experiment Video
Updated: Jan 23, 2026
09:20
Lumped-Parameter and Finite Element Modeling of Heart Failure with Preserved Ejection Fraction
Published on: February 13, 2021
7.0K
Automated proper lumping for simplification of linear physiologically based pharmacokinetic systems
Shan Pan1,2, Stephen B Duffull3
1School of Pharmacy, University of Otago, Dunedin, New Zealand. shan.pan@kcl.ac.uk.
Journal of Pharmacokinetics and Pharmacodynamics
|June 23, 2019
Summary
Physiologically based pharmacokinetic (PBPK) models can be simplified using lumping techniques. Simulated annealing (SA) proved most efficient for creating simpler PBPK models for drug development.
Area of Science:
- Pharmacokinetics and Drug Development
- Systems Biology and Computational Modeling
Background:
- Physiologically based pharmacokinetic (PBPK) models are crucial in early drug development but their complexity hinders population pharmacokinetic (PK) analyses.
- Simplifying complex PBPK models is necessary for their application in data-driven PK studies.
Purpose of the Study:
- To explore and automate methods for simplifying linear PBPK models using a proper lumping technique.
- To evaluate the efficiency and robustness of different simplification methods, including simulated annealing (SA).
Main Methods:
- Developed four methods to simplify a 17-state linear fentanyl PBPK model: full enumeration, non-adaptive random search (NARS), scree plot plus NARS, and simulated annealing (SA).
- A criterion was set for the lumped model's area under the concentration-time curve (AUC) to differ by a maximum of 0.002% from the original model.
Main Results:
- Full enumeration identified a 4-state lumped model. NARS also found a lumped model but required extensive sampling.
- The scree plot method accelerated NARS. Simulated annealing (SA) consistently delivered a 4-state lumped model.
- SA demonstrated robustness and efficiency in simplifying the fentanyl PBPK model.
Conclusions:
- Simulated annealing is a robust and efficient method for simplifying linear PBPK models.
- Simplified PBPK models retain fundamental mechanisms and are suitable for data-driven PK analyses.
- The SA approach may be broadly applicable to other large-scale linear systems.
Related Concept Videos
01:23Linear time-invariant Systems
887
A system is linear if it displays the characteristics of homogeneity and additivity, together termed the superposition property. This principle is fundamental in all linear systems. Linear time-invariant (LTI) systems include systems with linear elements and constant parameters.
The input-output behavior of an LTI system can be fully defined by its response to an impulsive excitation at its input. Once this impulse response is known, the system's reaction to any other input can be...
The input-output behavior of an LTI system can be fully defined by its response to an impulsive excitation at its input. Once this impulse response is known, the system's reaction to any other input can be...
887
01:13Physiological Pharmacokinetic Models: Assumption with Protein Binding
226
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...
226
01:15Model Approaches for Pharmacokinetic Data: Physiological Models
252
Physiological models in pharmacokinetics are instrumental in understanding the distribution and elimination of drugs within the body. These models describe the drug concentration within target organs, influenced by factors such as drug uptake, tissue volume, and blood flow. Drug uptake is governed by the partition coefficient, which signifies the drug concentration ratio in tissue to that in the blood. The blood flow rate to a specific tissue is expressed as Qt, and the rate of change in tissue...
252
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
281
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,...
A recent model describes pravastatin's hepatobiliary excretion,...
281
01:18Simplification of a Force and Couple System I
936
The concept of reducing a system of forces and couple moments to an equivalent system is essential in simplifying the analysis of rigid bodies. This reduction allows for more straightforward computation and understanding of the external effects produced by the system. In particular, systems with an equivalent resultant force and a resultant couple moment having perpendicular lines of action can be further reduced to a single equivalent resultant force acting along a new line of action. There...
936
01:23Simplification of a Force and Couple System: II
590
In a three-dimensional system, multiple forces can act on an object. These forces can be combined into a single equivalent force, known as the resultant force. Similarly, the moments generated by these forces can be combined into a single equivalent moment, the resultant couple moment. In certain situations, these two entities may not be mutually perpendicular, meaning they do not have a 90-degree angle between them. This unique condition requires a deeper understanding of the interplay between...
590