Chronic liver disease Long-term liver disease
Conditions
Interventions
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 m
Sponsors
Amsterdam UMC
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Age = 18 years Clinical, radiological and/or histological diagnosis of cirrhosisInformed consent signed prior to participation in the study
Exclusion criteria
Exclusion criteria: Original MELD score > 30Estimated creatinine clearance < 30 mL/min, calculated by using the Cockcroft-Gault equationKnown 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 cocktailRecent 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):caffeine: 5h x 5 = 25 hourswarfarin: 50h x 5 = 250 hoursesomeprazole: 1.3h x 5 = 6.5 hoursmetoprolol: 3.5h x 5 = 17.5 hoursmidazolam: 2.5h x 5 = 12.5 hours Absolute contraindication for one of the drugs in the probe drug cocktail:caffeine: drug hypersensitivitywarfarin: drug hypersensitivity and active bleedingesomeprazole: drug hypersensitivity, congenital long QT syndrome and suspected gastrointestinal malignancymetoprolol: 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 pheochromocytomamidazolam: drug hypersensitivity, severe chronic obstructive pulmonary disease, myasthenia gravis, sleep apnoea syndrome requiring CPAP, Parkinson's disease, severe respiratory insufficiency or acute respiratory depressionInteractions 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)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 managedRefusing or unable to give informed consent (e.g. hepatic encephalopathy)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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. | — |
Countries
Netherlands
Contacts
Public ContactS Ezzafzafi
Amsterdam UMC
Outcome results
None listed