Annika R. P. Schneider(1,2), Rolf Burghaus(2), Katrin Coboeken(2), Christian Diedrich(2), Joerg Lippert(3), Hannah Mayer(2), Jan-Frederik Schlender(2), Lars Kuepfer(2)
(1) Institute of Applied Microbiology, RWTH Aachen University, Germany (2) Systems Pharmacology & Medicine, Bayer AG, Leverkusen, Germany (3) Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany
Objectives:
Liver cirrhosis is a disease in which the functionality of the liver decreases with disease progression. Severe morphological and physiological alterations that are known to substantially affect drug pharmacokinetics (PK) are associated. Nevertheless, the extents to which the different alterations affect the PK of which drug are rarely known and difficult to predict. A suitable tool to combine information on pathophysiology and evaluate the functional impact on drug PK is physiologically based pharmacokinetic (PBPK) modeling [1]. However, the needed quantification of physiological changes in liver cirrhosis is difficult due to a lack of appropriate data and limited understanding of disease progression. Additionally, the limited translatability of the common Child-Pugh grading into actual physiological parameters complicates this task.
The objective of the presented approach was to expand and refine a current PBPK model for liver cirrhosis [1]. The refined model has a special focus on disease progression as well as population distributions.
Methods:
In a first step, pathophysiological changes in cirrhosis patients were quantified in dependence of the Child-Pugh score. Two different resources were used for this purpose. Firstly, the IBM® “Explorys” database [2] of real-world medical data was used. The patients in the database were classified by the Child-Pugh score. Distributions for several pathophysiological changes were extracted for all possible scores. Secondly, physiological changes that could not be informed by the database were informed using literature data. Literature data often comes as various types of aggregated or individual data. To cope with the mixture of data types, a Markov chain Monte Carlo (MCMC) approach [3] was performed to fit a function (and a corresponding prediction interval) that describes the change of the physiological parameter in relation to the Child-Pugh score. In the end, distributions were extracted from these functions for all possible scores.
In a second step, the pathophysiological changes were integrated into a PBPK model. Simulations for several compounds with different properties were performed and compared to literature data. PBPK modeling was performed using PK-Sim® as part of the Open Systems Pharmacology Suite [4] and the included MATLAB toolbox.
Results:
The quantifications of all studied pathophysiological changes behave as expected regarding the direction of change (increase or decrease) during disease progression. Simulation results of several compounds with different pharmacokinetic properties specifically chosen to test single pathophysiological changes or combinations show good agreement with literature data for the tested parameters like for example enzyme kinetics for CYP3A4, albumin, hematocrit and body composition including ascites.
Conclusions:
In this study, an expanded and refined PBPK model for liver cirrhosis patients is presented. The model considers continuous disease progression while keeping the relation to the Child-Pugh grading system. This allows to examine the heterogeneity of cirrhotic populations regarding pathophysiological alterations and consequent changes in drug PK. In a next step, more compound simulations will be performed in a structured approach to finally validate the model. In the future, this model will allow improved in silico trial simulations in cirrhotic patient cohorts and, thus, will be a helpful tool for the evaluation of drug efficacy and safety.
References:
[1] Edginton, A.N. and S. Willmann, Clin Pharmacokinet., 2008; 47(11):743-52.
[2] https://www.ibm.com/downloads/cas/6VQK0DLL
[3] PAGE 27 (2018) Abstr 8583 [www.page-meeting.org/?abstract=8583
[4] http://www.open-systems-pharmacology.org/
Reference: PAGE () Abstr 9444 [www.page-meeting.org/?abstract=9444]
Poster: Drug/Disease Modelling - Absorption & PBPK