S3-Leitlinie „Prophylaxe, Diagnostik und Therapie der Hepatitis-C-Virus (HCV) -Infektion“ : AWMF-Register-Nr.: 021/012

A Model‐Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs

We present a generic workflow combining physiology-based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology-based bile acid model of glycochenodeoxycholic acid. The simulated drug-induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholest…

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of alter…

Prophylaxis, diagnosis and therapy of Hepatitis C Virus (HCV) infection : The German guidelines on the management of HCV infection