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

NCT02353455 | Unknown

• 1 other identifier: 055-13
• Study Type: observational
• Target: 300
• Locations: 5 countries
• Sites: 5

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.

Conditions

Drug-induced Disorder of Liver; Adverse Reaction to Drug

Outcome Measures

Primary Outcomes (1)

• Reflection of individual drug hepatotoxicity in monocyte derived cells

  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.

  12 months

Study Arms (4)

healthy

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.

Procedure: Blood sampling

prior to therapy

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.

Procedure: Blood sampling

iDILI

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.

Procedure: Blood sampling

non DILI

Patients with other forms of liver injury. After pseudonymisation a detailed history and clinical data are obtained and blood sampling will be performed.

Procedure: Blood sampling

Interventions

Blood sampling PROCEDURE

In each group a blood sample of approximately 50 mL will be obtained upon study inclusion.

healthy; iDILI; non DILI; prior to therapy

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The groups or cohorts will be selected from patients treated at the LMU University Hospital. Sampling Method is non-probability sample: patients are invited to volunteer to participate.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Andreas Benesic, MD: lead
• MetaHeps GmbH: collaborator

Study Sites (5)

Gastroenterology, Alfred Health

Melbourne, Victoria, Australia

RECRUITING

Liver Center Munich®, Department of Internal Medicine II, LMU University Hospital, Campus Grosshadern

Munich, Bavaria, 81377, Germany

RECRUITING

Chinese University of Hong Kong

Hong Kong, Hong Kong

RECRUITING

Department of Gastroenterology and Hepatology Nagoya University School of Medicine

Nagoya, Japan

RECRUITING

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine

Seoul, South Korea

RECRUITING

Related Publications (15)

• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004 Aug;10(8):1018-23. doi: 10.1002/lt.20204.

  PMID: 15390328 BACKGROUND

• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008 Dec;135(6):1924-34, 1934.e1-4. doi: 10.1053/j.gastro.2008.09.011. Epub 2008 Sep 17.

  PMID: 18955056 BACKGROUND

• Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006 Mar;43(3):618-31. doi: 10.1002/hep.21095.

  PMID: 16496329 BACKGROUND

• Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology. 2010 Jun;138(7):2246-59. doi: 10.1053/j.gastro.2010.04.001. Epub 2010 Apr 12.

  PMID: 20394749 BACKGROUND

• Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003 Jul 31;349(5):474-85. doi: 10.1056/NEJMra021844. No abstract available.

  PMID: 12890847 BACKGROUND

• Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009 Nov;29(4):337-47. doi: 10.1055/s-0029-1240002. Epub 2009 Oct 13.

  PMID: 19826967 BACKGROUND

• Zimmerman HJ. Drug-induced liver disease. Drugs. 1978 Jul;16(1):25-45. doi: 10.2165/00003495-197816010-00002.

  PMID: 352664 BACKGROUND

• Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155-64. doi: 10.1080/01926230590522356.

  PMID: 15805067 BACKGROUND

• Fannin RD, Russo M, O'Connell TM, Gerrish K, Winnike JH, Macdonald J, Newton J, Malik S, Sieber SO, Parker J, Shah R, Zhou T, Watkins PB, Paules RS. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology. 2010 Jan;51(1):227-36. doi: 10.1002/hep.23330.

  PMID: 19918972 BACKGROUND

• Benesic A, Rahm NL, Ernst S, Gerbes AL. Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies. Lab Invest. 2012 Jun;92(6):926-36. doi: 10.1038/labinvest.2012.64. Epub 2012 Apr 2.

  PMID: 22469698 BACKGROUND

• Weber S, Erhardt F, Allgeier J, Saka D, Donga N, Neumann J, Lange CM, Gerbes AL. Drug-Induced Liver Injury Caused by Metamizole: Identification of a Characteristic Injury Pattern. Liver Int. 2025 Mar;45(3):e70012. doi: 10.1111/liv.70012.

  PMID: 39912769 DERIVED

• Weber S, Benesic A, Neumann J, Gerbes AL. Liver Injury Associated with Metamizole Exposure: Features of an Underestimated Adverse Event. Drug Saf. 2021 Jun;44(6):669-680. doi: 10.1007/s40264-021-01049-z. Epub 2021 Feb 27.

  PMID: 33638811 DERIVED

• Benesic A, Jalal K, Gerbes AL. Drug-Drug Combinations Can Enhance Toxicity as Shown by Monocyte-Derived Hepatocyte-like Cells From Patients With Idiosyncratic Drug-Induced Liver Injury. Toxicol Sci. 2019 Oct 1;171(2):296-302. doi: 10.1093/toxsci/kfz156.

  PMID: 31407002 DERIVED

• Benesic A, Rotter I, Dragoi D, Weber S, Leitl A, Buchholtz ML, Gerbes AL. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. Clin Gastroenterol Hepatol. 2018 Sep;16(9):1488-1494.e5. doi: 10.1016/j.cgh.2018.04.049. Epub 2018 Apr 30.

  PMID: 29723689 DERIVED

• Benesic A, Leitl A, Gerbes AL. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut. 2016 Sep;65(9):1555-63. doi: 10.1136/gutjnl-2015-309528. Epub 2015 Jun 4.

  PMID: 26045135 DERIVED

Related Links

• Homepage Liver Center Munich

Biospecimen

Retention: SAMPLES WITHOUT DNA

PBMC samples, monocyte derived cells

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Alexander L Gerbes, Prof. MD

  Liver Center Munich®, Internal Medicine II, Ludwig-Maximilians University Hospital, Campus Grosshadern, Munich; Marchioninistr. 15; D81377 Munich, Germany

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andreas Benesic, MD

CONTACT

+49 89 44007; andreas.benesic@med.uni-muenchen.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr. med.

Study Record Dates

• First Submitted: January 28, 2015
• First Posted: February 2, 2015
• Study Start: March 1, 2013
• Primary Completion: March 1, 2020
• Study Completion: August 1, 2022
• Last Updated: November 26, 2019

Record last verified: 2019-11

Locations

DE (1); JP (1); KR (1); AU (1); HK (1)