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Azathioprine response

MedGen UID:
450431
Concept ID:
CN077959
Sign or Symptom
Synonyms: Imuran response
Drug:
Azathioprine
MedGen UID:
13991
Concept ID:
C0004482
Pharmacologic Substance
an immunosuppressive drug
 
Gene (location): TPMT (6p22.3)

Definition

The thiopurines include azathioprine (a pro-drug for mercaptopurine), mercaptopurine and thioguanine. They are used to treat a variety of immunological disorders such as rheumatoid arthritis, non- Hodgkin lymphoma and ulcerative colitis. Both mercaptopurine and thioguanine can exert cytotoxic effects through the formation of thioguanine nucleotides (TGNs), active metabolites that incorporate into DNA. Mercaptopurine and thioguanine are directly inactivated by thiopurine S-methyltransferase (TPMT). Individuals with two nonfunctional TPMT alleles are at 100% risk of potentially fatal myelosuppression, due to an increased buildup of toxic TGNs. Alternative agents or a drastically reduced dose are recommended for patients with this genotype. Patients heterozygous for a nonfunctional TPMT allele are at increased risk of myelosuppression, and reduced dosing is recommended for these individuals. These dosing guidelines have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Additional descriptions

From Medical Genetics Summaries
Azathioprine is an immunosuppressant that belongs to the drug class of thiopurines. It is used in combination with other drugs to prevent kidney transplant rejection and in the management of rheumatoid arthritis when other treatments have not been effective. In addition, off-label uses include the treatment of inflammatory bowel disease. Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. Thiopurine S-methyltransferase (TPMT) inactivates azathioprine, leaving less parent drug available to form TGNs. An adverse effect of azathioprine therapy is bone marrow suppression, which can occur in any patient, is dose-dependent, and may be reversed by reducing the dose of azathioprine. However, patients who carry two nonfunctional TPMT alleles universally experience life-threatening myelosuppression when treated with azathioprine, due to high levels of TGNs. Patients who carry one nonfunctional TPMT allele may also be unable to tolerate conventional doses of azathioprine. The FDA recommends TPMT genotyping or phenotyping before starting treatment with azathioprine. This allows patients who are at increased risk for toxicity to be identified and for the starting dose of azathioprine to be reduced, or for an alternative therapy to be used. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published recommendations for TPMT genotype-based azathioprine dosing. These recommendations include: Consider an alternate agent or extreme dose reduction of azathioprine for patients with low or deficient TPMT activity. Start at 30-70% of target dose for patients with intermediate enzyme activity.  https://www.ncbi.nlm.nih.gov/books/NBK100661
From NCBI curation
The thiopurines include azathioprine (a pro-drug for mercaptopurine), mercaptopurine and thioguanine. They are used to treat a variety of immunological disorders such as rheumatoid arthritis, non- Hodgkin lymphoma and ulcerative colitis. Both mercaptopurine and thioguanine can exert cytotoxic effects through the formation of thioguanine nucleotides (TGNs), active metabolites that incorporate into DNA. Mercaptopurine and thioguanine are directly inactivated by thiopurine S-methyltransferase (TPMT). Individuals with two nonfunctional TPMT alleles are at 100% risk of potentially fatal myelosuppression, due to an increased buildup of toxic TGNs. Alternative agents or a drastically reduced dose are recommended for patients with this genotype. Patients heterozygous for a nonfunctional TPMT allele are at increased risk of myelosuppression, and reduced dosing is recommended for these individuals. These dosing guidelines have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.

Term Hierarchy

Professional guidelines

PubMed

Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE; Clinical Pharmacogenetics Implementation Consortium.
Clin Pharmacol Ther 2013 Apr;93(4):324-5. Epub 2013 Jan 17 doi: 10.1038/clpt.2013.4. PMID: 23422873Free PMC Article
Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE; Clinical Pharmacogenetics Implementation Consortium.
Clin Pharmacol Ther 2011 Mar;89(3):387-91. Epub 2011 Jan 26 doi: 10.1038/clpt.2010.320. PMID: 21270794Free PMC Article

External

National Academy of Clinical Biochemistry, Clinical practice considerations. In: Laboratory medicine practice guidelines: guidelines and recommendations for laboratory analysis and application of pharmacogenetics to clinical practice, 2010

Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk

Recent clinical studies

Etiology

Thompson AJ, Newman WG, Elliott RA, Roberts SA, Tricker K, Payne K
Value Health 2014 Jan-Feb;17(1):22-33. doi: 10.1016/j.jval.2013.10.007. PMID: 24438714
Bourgine J, Garat A, Allorge D, Crunelle-Thibaut A, Lo-Guidice JM, Colombel JF, Broly F, Billaut-Laden I
Pharmacogenet Genomics 2011 Jun;21(6):313-24. doi: 10.1097/FPC.0b013e3283449200. PMID: 21372752
Chebli LA, Felga GG, Chaves LD, Pimentel FF, Guerra DM, Gaburri PD, Zanini A, Chebli JM
Med Sci Monit 2010 Feb;16(2):PI1-6. PMID: 20110928
Chocair PR, Duley JA, Sabbaga E, Arap S, Simmonds HA, Cameron JS
Q J Med 1993 Jun;86(6):359-63. PMID: 8171183

Therapy

Thompson AJ, Newman WG, Elliott RA, Roberts SA, Tricker K, Payne K
Value Health 2014 Jan-Feb;17(1):22-33. doi: 10.1016/j.jval.2013.10.007. PMID: 24438714
Bourgine J, Garat A, Allorge D, Crunelle-Thibaut A, Lo-Guidice JM, Colombel JF, Broly F, Billaut-Laden I
Pharmacogenet Genomics 2011 Jun;21(6):313-24. doi: 10.1097/FPC.0b013e3283449200. PMID: 21372752
Chebli LA, Felga GG, Chaves LD, Pimentel FF, Guerra DM, Gaburri PD, Zanini A, Chebli JM
Med Sci Monit 2010 Feb;16(2):PI1-6. PMID: 20110928
Chocair PR, Duley JA, Sabbaga E, Arap S, Simmonds HA, Cameron JS
Q J Med 1993 Jun;86(6):359-63. PMID: 8171183

Prognosis

Chebli LA, Felga GG, Chaves LD, Pimentel FF, Guerra DM, Gaburri PD, Zanini A, Chebli JM
Med Sci Monit 2010 Feb;16(2):PI1-6. PMID: 20110928

Clinical prediction guides

Chebli LA, Felga GG, Chaves LD, Pimentel FF, Guerra DM, Gaburri PD, Zanini A, Chebli JM
Med Sci Monit 2010 Feb;16(2):PI1-6. PMID: 20110928

Therapeutic recommendations

This section contains excerpted1information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2015 Statement from the US Food and Drug Administration (FDA): TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZATHIOPRINE. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life threatening myelotoxicity from azathioprine if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). Azathioprine should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.

Please review the complete therapeutic recommendations that are located here: (1).

2013 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC): Testing for TPMT status is recommended prior to starting azathioprine therapy so that the starting dosages can be adjusted accordingly—see Table 1 for dosing recommendations. In homozygous variant individuals, either an alternative agent should be used, or the doses of azathioprine should be drastically reduced. In heterozygous individuals, depending on the disease being treated, starting doses should be reduced. In both patient groups, a longer period of time should be left after each dose adjustment to allow for a steady state to be reached.

Please review the complete therapeutic recommendations that are located here: (3, 4).

Table 1. TPMT phenotypes and the therapeutic recommendations for azathioprine therapy, adapted from CPIC
The strength of therapeutic recommendations is “strong” for all phenotypes. Table is adapted from Relling M.V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clinical pharmacology and therapeutics. 2011;89(3):387–91 (3, 4).
PhenotypePhenotype detailsTPMT
Genotype
Examples of diplotypesTherapeutic recommendations for azathioprine
Homozygous wild-type (“normal”)High enzyme activity.
Found in ~86–97% of patients.
Two or more functional TPMT alleles*1/*1Start with normal starting dose (e.g., 2–3 mg/kg/d) and adjust doses of azathioprine based on disease-specific guidelines.
Allow 2 weeks to reach steady state after each dose adjustment.
HeterozygousIntermediate enzyme activity.
Found in ~3–14% of patients.
One functional TPMT allele plus one nonfunctional TPMT allele*1/*2
*1/*3A
*1/*3B
*1/*3C
*1/*4
If disease treatment normally starts at the “full dose”, consider starting at 30–70% of target dose (e.g., 1–1.5 mg/kg/d), and titrate based on tolerance.
Allow 2–4 weeks to reach steady state after each dose adjustment.
Homozygous variantLow or deficient enzyme activity.
Found in ~1 in 178 to 1~3736 patients.
Two nonfunctional TPMT alleles*3A/*3A
*2/*3A
*3C/*3A
*3C/*4
*3C/*2
*3A/*4
Consider alternative agents. If using azathioprine start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines.
Allow 4–6 weeks to reach steady state after each dose adjustment.
Azathioprine is the likely cause of myelosuppression.

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labelled all formulations containing the generic drug.

1. AZATHIOPRINE- azathioprine tablet [package insert]. Mahwah, NJ: Glenmark Pharmaceuticals Inc.; 2015. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ceab8e8b-d022-4d0c-a552-cc5782446248

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