Page 136 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Supplementary Table 7. Suggested clinical decision support texts for various health care professionals for 5-FU/capecitabine
DPD gene act. 0: 5-fluorouracil (5-FU)/capecitabine, SYSTEMIC
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 standard dose is a more than 100-fold overdose.
Recommendation:
- Choose an alternative
Tegafur is not an alternative, as this is also metabolised by DPD.
- If an alternative is not possible:
o o
Determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly.
A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped)
The average Caucasian DPD activity is 9.9 nmol/hour per mg protein. Adjust the initial dose based on toxicity and efficacy.
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 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:
5-Fluorouracil and its prodrug capecitabine are 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:
All patients with gene activity score 0 with known toxicity (n=2, both *2A/*2A), had grade III/IV toxicity and 50% died due to toxicity. Moreover, a patient with *2A/*2A developed severe toxicity after treatment with cutaneous 5-fluorouracil cream.
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).
Literature
1. Rosmarin D et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 2014; 32:1031-9.
2. Deenen MJ et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17:3455-68.
3. Gross E et al. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS ONE 2008;3:e4003.
4. 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.
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