Correlation of Genetic Polymorphism of Azathioprine Metabolizing Enzymes and Correlation to Clinical Adverse Effects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00525473
First received: September 3, 2007
Last updated: May 16, 2012
Last verified: January 2012
  Purpose

Azathioprine (AZA) has long been used in dermatology in treating autoimmune bullous dermatoses and generalized eczematous disorders as well as some photodermatoses. Its metabolic process inside human body and its side effects relies on genetic polymorphism of some enzymes such as thiopurine s-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase gene (ITPA). This study aims to analyze the relative contribution of TMPT and ITPA mutations to the development of toxicity induced by AZA treatment and to detect the correlation of the genetic polymorphism.


Condition Intervention
Azathioprine
Thiopurine Methyltransferase
Inosine Triphosphate Pyrophosphatase
Genetic Polymorphism
Drug: Azathioprine

Study Type: Observational
Study Design: Time Perspective: Retrospective
Official Title: Correlation of Genetic Polymorphism of Two Azathioprine Metabolizing Enzymes and Their Correlation to Clinical Adverse Effects

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Primary Outcome Measures:
  • Genetic polymorphism tests before azathioprine therapy may reduce toxicity [ Time Frame: 2008.1.1 ] [ Designated as safety issue: Yes ]
    current treatment to nausea/vomiting adverse effects induced by azathioprine combined with pre-therapeutic genetic screening, especially polymorphism ITPA C94A, may reduce the possibility for developing hematopoietic toxicity and/or hepatotoxicity.


Enrollment: 166
Study Start Date: February 2007
Study Completion Date: January 2008
Primary Completion Date: December 2007 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Azathioprine
    azathioprine usual dosage 100mg per day
    Other Name: azathioprine
Detailed Description:

Dermatologists have been using azathioprine for more than 30 years. This synthetic purine analog is derived from 6-mercaptopurine. It is thought to act by disrupting nucleic acid synthesis and has recently been found to interfere with T-cell activation. The most recognized uses of azathioprine in dermatology are for immunobullous diseases, generalized eczematous disorders, and photodermatoses. Azathioprine is extensively metabolized, and only about 2% is excreted, unchanged, in the urine. Once freed of its imidazole derivative, the mercaptopurine moiety undergoes metabolism from 3 competing enzymes. Activity of the 2 catabolic enzymes thiopurine s-methyltransferase (TPMT), an enzyme with great genetic polymorphism, and xanthine oxidase (XO) produces inactive metabolites. Decreased TPMT or XO activity results in the increased production of toxic metabolites. Decreased TPMT activity is frequently a consequence of genetic polymorphisms, while decreased XO activity may be mediated by medications such as allopurinol.

Azathioprine is generally well tolerated and has a favorable therapeutic index compared with many other traditional immunosuppressants. Dose-limiting toxicity from azathioprine treatment affects up to 37% of patients. Administration of azathioprine to a patient with TPMT deficiency results in significant accumulation of thioguanine nucleotides, and it becomes clinically manifest by increased hematopoietic toxicity, with potentially grave consequences. Screening for thiopurine methyltransferase (TPMT) polymorphisms, TPMT*3A, *3C, *2 will prospectively identify approximately 10% of patients. In Chinese, the reported incidence of homozygous wild-type、heterozygote、homozygous mutation of TPMT is 95.3%, 4.7% and 0% respectively. The relationship to hematologic complication is more established, but its relationship to gastrointestinal side effects is controversial. Genetic polymorphism of the other newly identified enzyme, inosine triphosphate pyrophosphatase gene (ITPA) has also been associated with other adverse effect of azathioprine, such as flu-like symptoms, rash and pancreatitis. ITPA 94C>A allele is found at low frequency in Central/South American populations (1-2%), at a constant frequency across Caucasian and African populations (6-7%), and is highest in Asian populations (14-19%).

The aim of our study was to determine the relative contribution of, TMPT(A719G) and ITPA(C94A) mutations to the development of toxicity induced by AZA treatment in dermatology patients and to detect the correlation of these two genetic polymorphism.

Hepatotoxicity was defined by serum alanine transaminase levels greater than twice the upper normal limit (50 IU/l) and resolution after withdrawal of AZA; pancreatitis by severe abdominal pain and serum amylase > 800 IU/l; neutropenia by a neutrophil count of < 2.0 × 109 cells.

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Chinese Han patients

Criteria

Inclusion Criteria:

  • Patients who have used or are using azathioprine in treating skin diseases will be asked about treatment effects and adverse events.

Exclusion Criteria:

  • No special exclusion criteria
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00525473

Locations
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 100
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
Principal Investigator: Tsen-Fang Tsai, MD National Taiwan University Hospital
  More Information

No publications provided

Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT00525473     History of Changes
Other Study ID Numbers: 200701077M
Study First Received: September 3, 2007
Last Updated: May 16, 2012
Health Authority: Taiwan: Department of Health

Additional relevant MeSH terms:
Azathioprine
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014