Page 144 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Literature
1. Cubero DI et al. Tegafur-uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle. Ther Adv Med Oncol 2012;4:167- 72.
2. Deenen MJ et al. Standard-dose tegafur combined with uracil is not safe treatment after severe toxicity from 5-fluorouracil or capecitabine. Ann Intern Med 2010;153:767-8.
3. SPC Teysuno.
DPD gene act. 1.0: tegafur
Pharmacist text / Hospital text / Prescriber text
Genetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur into inactive metabolites means that the normal dose is an overdose.
Recommendation:
- Choose an alternative or start with a low dose and adjust the initial dose based on toxicity and efficacy
5-Fluorouracil and capecitabine are not alternatives, as these are also metabolised by DPD.
It is not possible to offer substantiated advice for dose reduction based on the literature. For 5-fluorouracil and capecitabine, starting with 50 % of the standard dose is recommended.
NOTE: If a patient has two different gene variations that result in a partially functional DPD enzyme (e.g. 2846T and 1236A), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, the gene activity score is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring the enzyme activity (phenotyping).
Background information
Mechanism:
Tegafur is mainly converted by CYP2A6 to 5-fluorouracil. 5-Fluorouracil is mainly (> 80 %) converted by dihydropyrimidine dehydrogenase (DPD) to inactive metabolites. Genetic variations result in reduced DPD activity and thereby to reduced conversion of 5-fluorouracil to inactive metabolites. As a result, the intracellular concentration of the active metabolite of 5-fluorouracil can increase, resulting in severe, potentially fatal toxicity. Tegafur is used in combination with the DPD inhibitor gimeracil (molar ratio 1:0.4) and was used in combination with the DPD inhibitor uracil (molar ratio 1:4). Both DPD inhibitors exhibit competitive inhibition of DPD. This is why efficacy is achieved at lower concentrations of the metabolites formed by DPD, which seem to contribute to the toxicity. Inhibition by DPD inhibitors is reversible and reduces over time.
For more information about the phenotype gene activity score 1: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for “DPD”).
Clinical consequences:
In a study, two patients had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-fluorouracil or capecitabine. In another study, four patients could be treated with 90 % of the standard tegafur/ uracil dose without grade 3-4 toxicity occurring. All six patients had the genotype *1/*2A.
Kinetic consequences:
There are no studies into the kinetic consequences.
Literature
1. Cubero DI et al. Tegafur-uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle. Ther Adv Med Oncol 2012;4:167- 72.
2. Deenen MJ et al. Standard-dose tegafur combined with uracil is not safe treatment after severe toxicity from 5-fluorouracil or capecitabine. Ann Intern Med 2010;153:767-8.
3. SPC Teysuno.
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