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

Genetic Polymorphism Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00525473
• Other study ID #: 200701077M
• Status: Completed
• Phase: N/A
• First received: September 3, 2007
• Last updated: May 16, 2012
• Start date: February 2007
• Est. completion date: January 2008

Study information

• Verified date: January 2012
• Source: National Taiwan University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 166
• Est. completion date: January 2008
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

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

Study Design

Time Perspective: Retrospective

Related Conditions & MeSH terms

• Azathioprine
• Genetic Polymorphism
• Inosine Triphosphate Pyrophosphatase
• Thiopurine Methyltransferase

Intervention

Drug:
• Azathioprine
azathioprine usual dosage 100mg per day

Locations

Country	Name	City	State
Taiwan	National Taiwan University Hospital	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Genetic polymorphism tests before azathioprine therapy may reduce toxicity	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.	2008.1.1	Yes