Page 125 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Supplementary Table 5. Dutch Pharmacogenetics Working Group (DPWG) Guideline for DPYD and 5-FU/capecitabine: the therapeutic recommendation and its rationale, and the kinetic and clinical consequences for each aberrant gene activity score
Predicted phenotype: Gene activity score 0 Ref. 1-13
Supplement
Therapeutic recommendation
SYSTEMIC ROUTE OF ADMINISTRATION:
Choose an alternative.
Tegafur is not an alternative, as this is also metabolised by DPD.
If an alternative is not available: determine the residual DPD activity in mononuclear cells 4 from peripheral blood and adjust the initial dose accordingly.
A patient with 0.5% of normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every five 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 carries 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 different alleles. If both variations are on the same allele, the patient is assigned a
gene activity score of 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).
CUTANEOUS ROUTE OF ADMINISTRATION:
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 is assigned a gene activity score of 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).
There are not enough data available to be able to make a substantiated recommendation on dose adjustments for patients assigned gene activity score 0. The recommendation for *1/*2A is a dose reduction by 50%. This would be equivalent to a dose reduction by 100% for *2A/*2A and therefore a dose reduction to 0%. This is equivalent to severe toxicity found in one patient with genotype *2A/*2A when using 5-FU cream on the scalp. Because of the indications that the tolerated dose is close to zero and the scarce data on tolerated doses in patients assigned a gene activity score of 0 (see below), an alternative is advised.
The calculated dose reduction based on two patients is a reduction to 0.81% of the normal dose (0.72-0.89%; median 0.81%). However, this is based on too few patients to be used
for a substantiated dose recommendation. In addition, in one of these patients, having undetectable DPD activity, the dose had to be reduced from 0.65% to 0.43% of the normal dose during treatment. However, there is a fairly good correlation between the residual DPD enzyme activity in peripheral blood mononuclear cells and the tolerated dose (Meulendijks 2016, Deenen 2016, Henricks 2017 JCO Precis Oncol and Henricks 2017 Int J Cancer). Therefore, if an alternative is not possible, adjusting the dose according to the residual DPD enzyme activity in peripheral blood mononuclear cells is advised. This strategy has been shown to be feasible in two patients with genotype *2A/*2A. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the normal dose (150 mg capecitabine every five days) (Henricks 2017 Int J Cancer). A patient with undetectable DPD activity, tolerated 0.43% of the normal dose (150 mg capecitabine every five days with every third dose skipped) (Henricks 2017 JCO Precis Oncol).
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Rationale of
the therapeutic recommendation
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