Page 126 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Kinetic consequence
Clinical consequence
For two patients with genotype *2A/*2A the dose-corrected AUC of 5-FU 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-FU 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).
SYSTEMIC ROUTE OF ADMINISTRATION:
All patients assigned a gene activity score of 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-FU cream.
CUTANEOUS ROUTE OF ADMINISTRATION:
A patient with *2A/*2A developed severe toxicity after treatment with cutaneous 5-FU cream. All patients using systemic 5-FU assigned a gene activity score of 0 with known toxicity (n=2, both *2A/*2A), had grade III/IV toxicity and 50% died due to toxicity.
Predicted phenotype: Gene activity score 0.5 Ref. 3-5,8-12,14,15
Therapeutic recommendation
Rationale of
the therapeutic recommendation
Kinetic consequence
Clinical consequence
Start with 25% of the standard dose or choose an alternative.
Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
NOTE: This recommendation only applies if the two genetic 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).
Clearance has only been determined for one patient assigned a gene activity score of 0.5 (Boisdron-Celle, 2007). The clearance found for this patient with genotype *2A/c.2846A>T was almost zero.
Extrapolation of the required dose reduction by 50% for *1/*2A and the required dose reduction by 25% for *1/c.2846A>T and *1/c.1236G>A would, however, lead to a required dose reduction by 75% for *2A/c.2846A>T. The dose reductions for *1/*2A, *1/2486T and *1/c.1236G>A are based on more than one patient. Moreover, the Boisdron-Celle article found a much lower clearance for one patient with genotype *1/*2A than the weighted average for this genotype (reduction by 80% instead of by 50%). For this reason, the recommendation given is based on extrapolation and therefore constitutes a dose reduction to 25% of the normal dose.
Instead of dose adjustment, physicians may also choose an alternative.
Clearance decreased by almost 100% in one patient assigned a gene activity score of 0.5 (*2A/c.2846A>T). Extrapolation of the dose reductions identified for *1/*2A, *1/c.2846A>T and *1/c.1236G>A would, however, lead to a dose reduction by 75%.
Clinical consequences are only known for three patients (all genotype *2A/c.2846A>T).
The first patient developed grade III/IV toxicity and died due to toxicity. The second patient developed grade V toxicity and tolerated only one cycle of FOLFOX plus cetuximab. The third patient received half of the standard dose, but despite this the fluoropyrimidine therapy was stopped after the first cycle due to side effects (≤ grade 3).
Predicted phenotype: Gene activity score 1 Ref. 1,3-6,8-12,14-39
Therapeutic recommendation
Start with 50% of the standard dose or choose an alternative.
Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
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