Predicting Response and Exposure Changes in Cirrhosis for Effectiveness

Обзор

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

Подробное описание

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)

Вмешательства

• Препарат 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.

Первичные конечные точки

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

Вторичные конечные точки (3)

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

Критерии участия

Критерии включения

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

Критерии исключения

• 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)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Другое

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07750587 · NL-011165 · NL-OMON61340

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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