Chemical: Prodrug
tegafur

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Prescribing Info (2) Drug Labels (0) Clinical Annotations (13)

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Dosing Guidelines

Annotation of CPIC Guideline for tegafur and DPYD
Annotation of DPWG Guideline for tegafur and DPYD

last updated 03/16/2017

1. Annotation of CPIC Guideline for tegafur and DPYD

Summary

The CPIC Dosing Guidelines for fluoropyrimidines (i.e. 5-fluorouracil, capecitabine or tegafur) recommends an alternative drug for patients who are homozygous for DPYD non-functional variants - *2A (rs3918290), *13 (rs55886062), and rs67376798 A (on the positive chromosomal strand) - as these patients are typically DPD deficient. Consider a 50% reduction in starting dose for heterozygous patients (intermediate activity).

Annotation

This annotation is based on the CPIC® guideline for fluoropyrimidines and DPYD.

May 2014 Update on PharmGKB

The CPIC authors recommend that the DPYD*4, *5, *6 and *9A alleles be categorized as "normal" activity, in part based upon the recent publication Comparative Functional Analysis of DPYD Variants of Potential Clinical Relevance to Dihydropyrimidine Dehydrogenase Activity.

December 2013 Publication

Accepted article preview online August 2013; Advance online publication October 2013.

Guidelines regarding the use of pharmacogenomic tests in dosing for fluoropyrimidines have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
These guidelines are applicable to:
- at the time of this writing, there are no data available on the possible role of DPYD*2A, *13, or rs67376798 in 5-fluorouracil toxicities in pediatric patient populations; however, there is no reason to suspect that DPYD variant alleles would affect 5-fluorouracil metabolism differently in children compared to adults.
Excerpt from the fluoropyrimidine dosing guideline based on DPYD genotype:
- "The strength of the dosing recommendations is based on the fact that some variants (DPYD*2A, *13, and rs67376798) clearly affect DPD activity, and DPD activity is clearly related to 5-fluorouracil clearance, and 5-fluorouracil exposure is associated with its toxic effects. Therefore, reduction of fluoropyrimidine dosage in patients with these variants may prevent severe and possibly life-threatening toxicities. However, available evidence does not clearly indicate a degree of dose reduction needed to prevent fluoropyrimidine related toxicities...[Based on literature review (see full manuscript),] our recommendation is to start with at least a 50% reduction of the starting dose followed by an increase in dose in patients experiencing no or clinically tolerable toxicity to maintain efficacy, a decrease in dose in patients who do not tolerate the starting dose to minimize toxicities or pharmacokinetic guided dose adjustments (if available). Patients who are homozygous for DPYD*2A, *13, or rs67376798 may demonstrate complete DPD deficiency and the use of 5-fluorouracil or capecitabine is not recommended in these patients."
Download and read:
- Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing
- 2013 supplement

Table 1: Recommended dosing of fluoropyrimidines by genotype/phenotype.

Adapted from Tables 1 and 2 of the 2013 guideline manuscript.

Phenotype (genotype)	Examples of diplotypes	Implications for phenotypic measures	Dosing recommendations	Classification of recommendations ^a
Homozygous wild-type or normal, high DPD activity (two or more functional *1 alleles)	1/1	Normal DPD activity and "normal" risk for fluoropyrimidine toxicity	Use label-recommended dosage and administration	Moderate
Heterozygous or intermediate activity (~3-5% of patients), may have partial DPD deficiency, at risk for toxicity with drug exposure (one functional allele 1, plus one nonfunctional allele - 2A, *13 or rs67376798A ^c)	1/2A; 1/13; *1/ rs67376798A ^c)	Decreased DPD activity (leukocyte DPD activity at 30% to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs	Start with at least a 50% reduction in starting dose followed by titration of dose based on toxicity ^b or pharmacokinetic test (if available)	Moderate
Homozygous variant, DPD deficiency (~0.2% of patients), at risk for toxicity with drug exposure (2 nonfunctional alleles - 2A, 13 or rs67376798A ^c)	2A/2A; 13/13; rs67376798A ^c / rs67376798A ^c	Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs	Select alternate drug	Strong

^a Rating scheme described in 2013 supplement.

^b Increase the dose in patients experiencing no or clinically tolerable toxicity to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.

^c Note that the rs67376798A allele refers to the allele on the positive chromosomal strand. This is important because DPYD is on the minus chromosomal strand and rs67376798 is a T/A snp. Therefore, the T allele on the gene confers the deficiency, while the complement on the positive chromosomal strand (A allele) is indicative of deficiency.

last updated 08/10/2011

2. Annotation of DPWG Guideline for tegafur and DPYD

Summary

Select an alternate drug (that is not metabolized by DPYD) rather than tegafur for DPYD poor metabolizers.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tegafur/uracil combination based on DPYD genotype [Article:21412232]. They recommend that an alternate drug be used for poor metabolizer patients, but do not provide a recommendation for intermediate metabolizer patients.

Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles)	Select alterantive drug. Fluorouracil or capecitabine are not suitable alternatives because both are also metabolized by DPD.	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 (NS). Kinetic effect (NS).
IM (1 active allele and 1 inactive or decreased activity allele)	None.	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 (NS). Kinetic effect (NS).

Allele Type	Alleles
active	1, 4, 5, 6, *9A
decreased activity	9B, 10
inactive	2A, 3, 7, 8, 11, 12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T

*See Methods or [Article:18253145] for definition of "moderate" quality.
NS: not statistically significant difference.

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