Predicting Response and Exposure Changes in Cirrhosis for Effectiveness

Overview

The goal of this clinical trial is to learn how liver cirrhosis affects the way the body processes drugs in adults with different stages of liver cirrhosis. This information may help improve drug dosing for people with liver cirrhosis in the future. The main question it aims to answer is: • How does the severity of liver cirrhosis affect the way the body processes a combination of five drugs, each used to measure the activity of a different liver enzyme? Researchers will compare participants with mild, moderate, and severe liver cirrhosis to see whether the processing of drugs differs between these groups. Participants will: * Fast overnight for 8 hours before receiving the drugs * Have a scan to measure the stiffness of their liver and spleen * Receive a single low dose of five drugs: caffeine, warfarin, esomeprazole, metoprolol, and midazolam * Have blood samples taken before and at several times up to 72 hours after receiving the drugs, including samples for genetic testing and blood clotting checks * Avoid caffeine-containing food and drinks from 48 hours before receiving the drugs until the final blood sample

Objective: to identify and quantify the effect of changes in liver-metabolism that occur in different grades of cirrhosis disease severity on the PK of five probe drugs that are each selectively metabolised by one CYP isoform using a probe drug cocktail as proxy. Study design: Single-dose interventional PK study Study population: 45 patients with (decompensated) cirrhosis, 18 years or older. Intervention: This study consists of a single intervention where patients receive a single oral administration of a drug probe cocktail. The oral probe drug cocktail consists of 100 mg caffeine, 5 mg warfarin, 20 mg esomeprazole, 50 mg metoprolol and 0.03 mg/kg midazolam. Main study parameters/endpoints: The primary endpoint is the unbound clearance (CL) of each parent of the probe drugs with the total and unbound area under the plasma concentration versus time curve (AUC) of each drug. Secondary endpoints include pharmacokinetic (PK) parameters such as volume of distribution of the central (V1) and peripheral compartment (V2) and intercompartment clearance (Q) of each probe drug. Secondary study parameters are: • To identify covariates that may influence PK changes in cirrhosis in the development of a population PK model: * Effect of different disease severity scores on PK (Model for End-stage Liver Disease (MELD) MELD, MELD-Na, MELD 3.0, reMELD-Na). * Effect of presence of portal hypertension (ascites, hepatic encefalopathie (HE), spontaneous bacterial peritonitis (SBP), variceal bleeding) * Effect of severity of portal hypertension on PK (spleen stiffness measurement; spleen stiffness measurement (SSM)) * Effect of inflammation on PK * Effect of acute-on-chronic liver failure (ACLF) on PK * Effect of concurrent acute kidney injury (AKI) on PK * Effect of plasma albumin and bilirubin on PK * Effect of CYP-polymorphisms on PK (metaboliser status and/or activity score of each CYP enzyme)