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

Detailed description

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 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 (MELD, MELD-Na, MELD 3.0, reMELD-Na). * Effect of presence of portal hypertension (ascites, HE, SBP, variceal bleeding) * Effect of severity of portal hypertension on PK (spleen stiffness measurement; SSM) * Effect of inflammation on PK * Effect of ACLF on PK * Effect of concurrent 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)

Interventions

• Drug Five-Drug CYP Probe Cocktail
  A single dose of a five-drug CYP probe cocktail consisting of caffeine 100 mg, warfarin 5 mg, esomeprazole 20 mg, metoprolol 50 mg, and midazolam 0.03 mg/kg.

Primary outcome measures

• Unbound clearance (CL) of each parent drug [Time frame: 24 months]
• Total and unbound area under the plasma concentration versus time curve (AUC) of each parent drug [Time frame: 24 months]

Secondary outcome measures (3)

• Volume of distribution of the central compartment (V1) of each parent drug [Time frame: 24 months]
• Volume of distribution of the peripheral compartment (V2) of each parent drug [Time frame: 24 months]
• Intercompartment clearance (Q) of each parent drug [Time frame: 24 months]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07750587 · NL-011165 · NL-OMON61340

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗