Page 143 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Clinical consequences:
There are no studies into the clinical consequences of tegafur in combination with a DPD inhibitor for gene activity score 0. The SmPC states that this combination is contra-indicated in patients with DPD deficiency. This probably refers to gene activity score 0. No safe dose has been found for gene activity score 0 for 5-fluorouracil (the metabolite of tegafur). In addition to this, four patients with a less strongly reduced DPD activity (gene activity score 1 or 1.5) had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-fluorouracil or capecitabine.
Kinetic consequences:
There are no studies into the kinetic consequences. 4
Literature
1. 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.
2. SPC Teysuno.
DPD gene act. 0.5: tegafur
Pharmacist text / Hospital text / Prescriber text
Genetic variation increases the risk of severe, possibly fatal toxicity. A reduced conversion of tegafur to 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 25% of the standard dose is recommended.
NOTE: This recommendation only applies if the two gene variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining 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 0.5: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for “DPD”).
Clinical consequences:
There are no studies into the clinical consequences of tegafur in combination with a DPD inhibitor for gene activity score 0.5. However, four patients with a less strongly reduced DPD activity (gene activity score 1 or 1.5) had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-fluorouracil or capecitabine. In addition to this, four patients with gene activity score 1 could be treated with 90 % of the standard tegafur/uracil dose without grade 3-4 toxicity occurring.
Kinetic consequences:
There are no studies into the kinetic consequences.
Supplement
141