Page 142 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
7. Boisdron-Celle M et al. 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Lett 2007;249:271-82.
8. Cho HJ et al. Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) polymorphisms in the Korean population for prediction of 5-fluorouracil-associated toxicity. Ther Drug Monit 2007;29:190-6.
9. Morel A et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006;5:2895-904.
10. Yamaguchi K et al. Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-fluorouracil. Jpn J Cancer Res 2001;92:337-42.
11. van Kuilenburg AB et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000;6:4705-12.
12. SPCs Efudix crème and Fluorouracil PCH.
Supplementary Table 8. Suggested clinical decision support texts for health care professionals for tegafur with DPD inhibitors
DPD gene act. 0: 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
Do not choose 5-fluorouracil or capecitabine, as these are also metabolised by DPD.
- If an alternative is not possible: start with a very low dose and adjust the initial dose based on toxicity
and efficacy.
A substantiated recommendation for dose reduction cannot be made based on the literature. The recommendation for 5-fluorouracil and capecitabine is to determine the residual DPD activity in mononuclear cells from peripheral blood and to adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard capecitabine dose (150 mg every 5 days).
A patient with undetectable DPD activity tolerated 0.43% of the standard capecitabine dose (150 mg every 5 days with every third dose skipped)
The average Caucasian DPD activity is 9.9 nmol/hour per mg protein.
NOTE: If a patient has two different gene variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the 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: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for “DPD”).
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