Annotation of DPWG Guideline for thioguanine and TPMT

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Summary

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

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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.

August 2019 Update

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine 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 updated the wording for the intermediate metabolizer recommendation, reflected in the table below.

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

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
TPMT IM	thioguanine	Genetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.	- IMMUNOSUPPRESSION: Start with 75% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. The frequency of monitoring should be increased. - LEUKAEMIA: Start with 75% of the standard thioguanine dose, or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction. It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity. The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy. Monitoring should be performed at an increased frequency. Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM.
TPMT PM	thioguanine	Genetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.	1. Choose an alternative or start with 6-7% 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) develop.

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

Preemptive genotyping

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

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

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	thioguanine	Genetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.	Start with 75% of the standard dose. Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy. The frequency of monitoring should be increased.
TPMT PM	thioguanine	Genetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious adverse events such as myelosuppression.	1. Choose an alternative or start with 6-7% 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) develop.

2011 Guideline

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug 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. Insufficient data to allow calculation of dose adjustment.	Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10⁹/l; leucopenia 1.0-2.0x10⁹/l; thrombocytopenia 25-50x10⁹/l; severe diarrhea.
PM (two inactive alleles: 2, 3, 4-18)	Select alternative drug. Insufficient data to allow calculation of dose adjustment.	Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series.	Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.

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

PharmGKB ID

PA166104960