Page 70 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
See Supplementary Table 7 and 8 for an overview of suggested pop-up texts for electronic prescribing systems for pharmacists and physicians. These can be used to program alerts into the clinical decision support system (CDSS). Spanish, Greek, Italian, German, Slovenian and Dutch translations of both the guidelines and background information are available on PharmGKB.org.
Implications for clinical practice
There is currently an ongoing debate regarding whether and which single-drug gene pairs should be implemented into routine care. Points of debate include the amount of evidence that is necessary supporting effectiveness of pre-emptive genotyping, the cost-effectiveness of the intervention and reimbursement of PGx testing.29,30 This inconclusive debate seems to have hampered implementation of drug-gene pairs which seem ready for implementation.1,31 In an effort to overcome this inconclusiveness and to direct clinicians on whether or not to order relevant PGx genotyping tests before initiating therapy, the DPWG has developed the clinical implication score. The pre-emptive PGx results for a certain drug-gene pair can be scored as: essential, beneficial, potentially beneficial or not required. The development of these categories and the systematic scoring criteria are discussed elsewhere.32 In brief, the implications for clinical practice are based on a list of four criteria regarding the following: the clinical effect associated with the gene-drug interaction, the level of evidence supporting the clinical effect, the effectiveness of the intervention in preventing the clinical effect (which includes the number needed to genotype) and the PGx information included in the drug-label. The scores provided for each of these criteria by the DPWG can be found in Supplementary Table 9.
As a result, the DPWG has concluded the clinical implication score of DPYD- fluoropyrimidines to be “essential”. This score dictates that DPYD genotyping prior to treatment must be performed for all patients initially being prescribed therapy with 5-FU, capecitabine or tegafur with DPD inhibitors, to optimize the initial dose and to prevent potentially fatal toxicity.
Differences between available guidelines
Other guidelines regarding the gene-drug interaction of DPYD and fluoropyrimidines have been developed. To the best of our knowledge, guidelines are available from CPIC,11,33 French (French Network of Pharmacogenetics, RNPGx)34 and Italian (Associazione Italiana di Oncologia Medica, AIOM-SIF) [unpublished guidelines, edited by the AIOM-SIF Working Group] initiatives. We have compared the DPWG guidelines to other available guidelines published in English. This regards only the CPIC guideline, since the French and Italian guidelines are unpublished or not in English.
CPIC
Differences between CPIC and DPWG methodology, genotype to phenotype conversion and recommendations have previously been described in detail.6 However, both guidelines have been updated.33,35 The current DPWG and CPIC guidelines5 for DPYD/fluoropyrimidines differ regarding the therapeutic recommendations. In contrast to CPIC, DPWG distinguishes
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