Predicting Response and Exposure Changes in Cirrhosis for Effectiveness

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

Inclusion Criteria: * Age ≥ 18 years * Clinical, radiological and/or histological diagnosis of cirrhosis * Informed consent signed prior to participation in the study Exclusion Criteria: * Original MELD score \> 30 * Estimated creatinine clearance \< 30 mL/min, calculated by using the Cockcroft-Gault equation * Known poor metaboliser status for one of the CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) described in the medical record * Previous clinically relevant adverse reaction or intolerance to one of the drugs in the probe drug cocktail * Recent exposure to one of the drugs in the drug probe cocktail within five elimination half-lives prior to drug administration (corresponding to approximately 1-10 days depending on the probe drug)36-40: * caffeine: 5h x 5 = 25 hours * warfarin: 50h x 5 = 250 hours * esomeprazole: 1.3h x 5 = 6.5 hours * metoprolol: 3.5h x 5 = 17.5 hours * midazolam: 2.5h x 5 = 12.5 hours * Absolute contraindication for one of the drugs in the probe drug cocktail36-40: * caffeine: drug hypersensitivity * warfarin: drug hypersensitivity and active bleeding * esomeprazole: drug hypersensitivity, congenital long QT syndrome and suspected gastrointestinal malignancy * metoprolol: drug hypersensitivity, cardiogenic shock, second- and third degree AV block, bradycardia (\< 50 beats per minute), sick sinus syndrome including SA block, symptomatic hypotension (mean arterial pressure \< 65 mmHg), metabolic acidosis and untreated pheochromocytoma * midazolam: drug hypersensitivity, severe chronic obstructive pulmonary disease, myasthenia gravis, sleep apnoea syndrome requiring CPAP, Parkinson's disease, severe respiratory insufficiency or acute respiratory depression * Interactions with strong to moderate CYP inhibitors and inducers of the following P450 enzymes: CYP1A2 (inhibitors: ciprofloxacin, fluvoxamine), CYP2C9, CYP2C19, CYP2D6 (inhibitors: bupropion, cinacalcet, fluoxetine, quinidine, paroxetine, terbinafine) and CYP3A (inducers: apalutamide, carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, lumacaftor, mitotane, nevirapine, primidone, rifabutin, rifampicin; inhibitors: clarithromycin, cobicistat, erythromycin, itraconazole, ketoconazole, posaconazole, ritonavir, voriconazole)41,42 * Use of concomitant medication with a clinically relevant PK or PD interaction with one or more components of the probe drug cocktail, if the interaction is expected to affect PK endpoint interpretation or compromise participant safety and cannot be appropriately managed * Refusing or unable to give informed consent (e.g. hepatic encephalopathy)