Page 137 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

5. 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.
6. Van Kuilenburg AB et al. High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 2002;12:555-8.
7. Raida M et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5’-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 2001;7:2832-9.
8. 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. 4
9. Johnson MR et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999;5:2006-11.
10. SPC Carac cream (VS), Efudix crème, Fluorouracil P and Xeloda.
DPD gene act. 0: 5-fluorouracil (5-FU) CUTANEOUS
Pharmacist text/ Hospital text / Prescriber text
Genetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of 5-fluorouracil/ capecitabine to inactive metabolites means that the normal dose is an overdose.
Recommendation:
- Choose an alternative
NOTE: If a patient has two different genetic 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, for which no increased risk of severe, potentially fatal toxicity has been found with cutaneous use. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
Background information
Mechanism:
5-Fluorouracil is mainly 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.
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).
Clinical consequences:
A patient with *2A/*2A developed severe toxicity after treatment with cutaneous 5-fluorouracil cream. All patients using systemic 5-fluorouracil with gene activity score 0 with known toxicity (n=2, both *2A/*2A), had grade III/IV toxicity and 50% died due to toxicity.
Kinetic consequences:
For 2 patients with genotype *2A/*2A the dose-corrected AUC of 5-fluorouracil increased by a factor 113 and 138 respectively after the first systemic capecitabine dose.
Extrapolation of the decrease in clearance by 50% identified for *1/*2A would suggest a clearance of 0% for *2A/*2A (gene activity score 0). This is equivalent to severe toxicity found in one patient with *2A/*2A after using 5-fluorouracil cream on the scalp and the two previously described patients using very low tolerated systemic doses (0.8% and 0.43% of the standard dose).
Supplement
135