Page 164 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
were treated with individualized fluoropyrimidine dosing or alternative treatment outside this study.17 However, for this group of patients DPYD genotype-guided dosing is of even greater importance than for heterozygous DPYD variant allele carriers, as these patients in general have less remaining DPD activity or even complete absence of DPD activity, and a full fluoropyrimidine dose, when not identified as DPD deficient patients, is therefore likely to be fatal.
Although our study revealed that the applied approach of genotype-guided adaptive dosing significantly reduced severe fluoropyrimidine-induced toxicity and prevented treatment related death, additional methods should be explored and prospectively tested to further reduce treatment related toxicity not only in poor metabolizers, but also in DPYD wild-type patients.
In conclusion, we showed safety of patients treated with fluoropyrimidines was improved by dose individualization based on DPYD genotype. Dose reduction of 50% in heterozygous DPYD*2A and c.1679T>G carriers reduced toxicity risk markedly. The applied dose reductions of 25% in heterozygous c.1236G>A and c.2846A>T carriers appear to be insufficient to lower the risk of fluoropyrimidine-related toxicity to the background risk in wild-type patients. A larger initial dose reduction of 50% for c.2846A>T and c.1236G>A carriers with subsequent individual dose titrations should therefore be considered.
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