Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity

• Conditions: Drug-induced Disorder of Liver; Adverse Reaction to Drug
• Interventions: Procedure: Blood sampling

• Registration Number: NCT02353455
• Lead Sponsor: Andreas Benesic, MD

Brief Summary

Drug metabolism in the liver is subject to large fluctuations (differences between women and men, people of different ethnic backgrounds, children and adults). These large differences are responsible for very different drug effects and side-effects (and especially liver damage caused by drugs) between individuals. Recent scientific findings suggest that blood derived cells can be used to model individual effects of drugs on the liver reflect inter-individual differences. Since liver damage caused by drugs is a diagnosis of exclusion, the aforementioned cells can be used to identify patients that show higher sensitivity to hepatotoxic side-effects and - in case several drugs are involved - identify the causal agent or possible interactions.

Detailed Description

Drug-induced liver injury (DILI), especially its idiosyncratic for is often an unpredictable complication of drug therapy. Until now it is very challenging to predict occurrence, severity and outcome of DILI. Previous data provide evidence that cells from peripheral blood may reflect hepatocellular damage (Fannin RD, Hepatology. 2010). Own research could show that peripheral monocytes are capable to obtain several hepatocyte-like functions while maintaining individual characteristics of the donor, especially cytochrome P450 metabolism (Benesic, Gerbes, et al, Lab Invest 2012). This study investigates the effects of potentially hepatotoxic drugs on cells generated from patient blood in comparison to the clinical presentation. Its aim is the evaluation of in vitro tests using monocyte derived cells for diagnosis and exclusion of DILI and the potential to use the patient derived-cells for mechanistic investigations of DILI. 4 groups are investigated: 1) donors without liver disease 2) patients who will start a therapy with DILI-potential; 3) DILI patients; 4) patients with liver injuries other than DILI.

Patient history and clinical data are obtained and a single blood sample will be collected after informed consent.

Study Timeline

• Study Start: 2013-03
• Study First Submitted: 2015-01-28
• Study First Submitted QC: 2015-01-28
• Study First Posted: 2015-02-02
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-23
• Last Update Posted: 2019-11-26
• Primary Completion: 2020-03
• Study Completion: 2022-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Age ≥ 2 years
• Informed consent given by the patient or in case of inability to give informed consent informed consent of the legally nominated consultee

Exclusion Criteria

• Anemia requiring blood transfusion
• acute or chronic hepatitis B, C or human immunodeficiency virus infection
• lack of informed consent

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
prior to therapy	Blood sampling	History will be obtained and blood sampling will be performed in patients in whom a drug therapy with a drug with DILI potential is planned.
healthy	Blood sampling	donors/patients without liver disease, with and without ongoing drug therapy including buffy coat samples of healthy blood / thrombocyte donors. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed . Buffy coats are obtained anonymously.
iDILI	Blood sampling	Patients with clinical suspicion of idiosyncratic drug-induced liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed.
non DILI	Blood sampling	Patients with other forms of liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed.

Primary Outcome Measures

Name	Time	Method
Reflection of individual drug hepatotoxicity in monocyte derived cells	12 months	After blood sampling, monocyte derived cells will be generated and tested in vitro for the respective compounds in short term and up to 4 weeks. If possible, the patient will have a clinical follow up during routine care to assess liver injury , course and outcome of the disease when applicable.

Trial Locations

Locations (5)

Department of Gastroenterology and Hepatology Nagoya University School of Medicine; 🇯🇵 Nagoya, Japan

Gastroenterology, Alfred Health; 🇦🇺 Melbourne, Victoria, Australia

Liver Center Munich®, Department of Internal Medicine II, LMU University Hospital, Campus Grosshadern; 🇩🇪 Munich, Bavaria, Germany

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine; 🇰🇷 Seoul, Korea, Republic of

Chinese University of Hong Kong; 🇭🇰 Hong Kong, Hong Kong