Annotation of DPWG Guideline for azathioprine and TPMT

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Summary

Select an alternative drug or reduce the initial dose of azathioprine for patients that are TPMT poor metabolizers and reduce initial dose for patients that are TPMT intermediate metabolizers.

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Alleles not present in the above pull-down menus have no recommendation.

Important information about alleles in DPWG guidelines.

Annotation

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

May 2020 Update

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype. They recommend reducing the initial dose for patients that are intermediate metabolizers and selecting an alternative drug or reducing the initial dose for patients that are poor metabolizers. They removed the sentence "The frequency of monitoring should be increased." from the previous recommendation.

Wording in table taken from the Dutch guidelines May 2020 update.

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
TPMT IM	azathioprine	Grade ≥ 2 leukopaenia occurs in 23% of these patients with normal therapy for immunosuppression. The genetic variation increases the quantity of the active metabolites of azathioprine and mercaptopurine.	-IMMUNOSUPPRESSION Start with 50% of the standard dose Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine. Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.
TPMT PM	azathioprine	Grade ≥ 2 leukopaenia and intolerance occurred in 98% of these patients with standard therapy. The gene variation increases the quantities of the active metabolites of azathioprine and mercaptopurine.	Choose an alternative or start with 10% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.

Read for more information about this recommendation. Read about gene information from DPWG

Preemptive genotyping

Excerpts from the DPWG risk analysis document for azathioprine and TPMT:

The Dutch Pharmacogenetics Working Group considers genotyping before starting azathioprine or 6-mercaptopurine to be essential for drug safety. Genotyping must be performed before drug therapy has been initiated to guide drug and dose selection.

August 2019 Update

Wording in table taken from the Dutch guidelines August 2019 update.

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
TPMT IM	azathioprine	The genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.	-IMMUNOSUPPRESSION Start with 50% of the standard dose Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine. Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM.
TPMT PM	azathioprine	The genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.	1. Choose an alternative or start with 10% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. 2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur

November 2018 Update

Wording in table taken from the Dutch guidelines November 2018 update.

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
TPMT IM	azathioprine	The genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.	Start with 50% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. Dose adjustment is not required for doses lower than 1.5 mg/kg per day for azathioprine or 0.75 mg/kg per day for mercaptopurine.
TPMT PM	azathioprine	The genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.	1. Choose an alternative or start with 10% of the standard dose.Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. The frequency of monitoring should be increased. 2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur.

2011 Guideline

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for azathioprine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug or reducing the initial dose for patients carrying inactive alleles.

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Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
IM (one inactive allele: 2, 3, 4-18)	Select alternative drug or reduce dose by 50%. Increase dose in response of hematologic monitoring and efficacy.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x10⁹/l; leucopenia < 1.0x10⁹/l; thrombocytopenia < 25x10⁹/l; life-threatening complications from diarrhea.
PM (two inactive alleles: 2, 3, 4-18)	Select alternative drug or reduce dose by 90%. Increase dose in response of hematologic monitoring and efficacy.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.

*See Methods or [Article:18253145] for definition of "good quality."
S: statistically significant difference.

PharmGKB ID

PA166104934