Predicting Response and Exposure Changes in Cirrhosis for Effectiveness

NCT07750587 | Not Yet Recruiting

• 2 other identifiers: NL-011165NL-OMON61340
• Study Type: interventional
• Target: 45
• Locations: 0 countries
• Sites: N/A

Brief Summary

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

Conditions

Liver Cirrhosis

Keywords

Pharmacokinetics; Drug metabolism; Cytochrome P450; Probe-drug cocktail; Cirrhosis; Hepatic impairment; CYP1A2; CYP2C9; CYP2C19; CYP2D6; CYP3A; Precision dosing

Outcome Measures

Primary Outcomes (2)

• Unbound clearance (CL) of each parent drug

  Unbound clearance (CL) of each parent drug

  24 months

• Total and unbound area under the plasma concentration versus time curve (AUC) of each parent drug

  Total and unbound area under the plasma concentration versus time curve (AUC) of each parent drug

  24 months

Secondary Outcomes (3)

• Volume of distribution of the central compartment (V1) of each parent drug

  24 months

• Volume of distribution of the peripheral compartment (V2) of each parent drug

  24 months

• Intercompartment clearance (Q) of each parent drug

  24 months

Study Arms (1)

Single-Dose Five-Drug CYP Probe Cocktail

OTHER

Participants with Child-Pugh class A, B, or C liver cirrhosis will receive the same single-dose combination of five CYP probe medicines. Pharmacokinetic outcomes will be compared between the three Child-Pugh classes.

Drug: Five-Drug CYP Probe Cocktail

Interventions

Five-Drug CYP Probe Cocktail DRUG

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.

Also known as: Caffeine, Warfarin, Esomeprazole, Metoprolol, Midazolam

Single-Dose Five-Drug CYP Probe Cocktail

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Clinical, radiological and/or histological diagnosis of cirrhosis
• Informed consent signed prior to participation in the study

You may not qualify if:

• 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

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

MeSH Terms

Conditions

Liver Cirrhosis; Fibrosis

Interventions

Caffeine; Warfarin; Esomeprazole; Metoprolol; Midazolam

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Omeprazole; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Benzimidazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Benzodiazepines; Benzazepines

Central Study Contacts

Marten A Lantinga, MD PhD

CONTACT

(+31) (0)20 444 4444; m.a.lantinga@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: dr.

Study Record Dates

• First Submitted: August 3, 2026
• First Posted: August 6, 2026
• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: August 6, 2026

Record last verified: 2026-08