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

Adverse Reaction to Drug Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02353455
• Other study ID #: 055-13
• Status: Recruiting
• Start date: March 2013
• Est. completion date: August 2022

Study information

• Verified date: November 2019
• Source: Ludwig-Maximilians - University of Munich
• Contact: Andreas Benesic, MD
• Phone: +49 89 44007
• Email: andreas.benesic[@]med.uni-muenchen.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: August 2022
• Est. primary completion date: March 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 2 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adverse Reaction to Drug
• Drug-induced Disorder of Liver
• Drug-Related Side Effects and Adverse Reactions
• Liver Diseases

Intervention

Procedure:
• Blood sampling
In each group a blood sample of approximately 50 mL will be obtained upon study inclusion.

Locations

Country	Name	City	State
Australia	Gastroenterology, Alfred Health	Melbourne	Victoria
Germany	Liver Center Munich®, Department of Internal Medicine II, LMU University Hospital, Campus Grosshadern	Munich	Bavaria
Hong Kong	Chinese University of Hong Kong	Hong Kong
Japan	Department of Gastroenterology and Hepatology Nagoya University School of Medicine	Nagoya
Korea, Republic of	Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Andreas Benesic, MD	MetaHeps GmbH

Countries where clinical trial is conducted

Australia,  Germany,  Hong Kong,  Japan,  Korea, Republic of, 

References & Publications (10)

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. Review. — View Citation

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. — View Citation

Chalasani N, Björnsson 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. Review. — View Citation

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. — View Citation

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. — View Citation

Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155-64. Review. — View Citation

Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003 Jul 31;349(5):474-85. Review. — View Citation

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. — View Citation

Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006 Mar;43(3):618-31. — View Citation

Zimmerman HJ. Drug-induced liver disease. Drugs. 1978 Jul;16(1):25-45. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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

External Links

•   Homepage Liver Center Munich