Page 146 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Supplementary Table 9. The clinical implication score of DPYD-fluoropyrimidines is “essential”, based on the criteria and corresponding scores given by the DPWG
Clinical Implication Score Criteria
Clinical effect associated with gene/drug interaction
3 (D) ≤ CTCAE Grade ≤4 (E) 4 (E) < CTCAE Grade ≤5 (F) Increased efficacy
Level of evidence supporting the associated clinical effect
One study with level of evidence score 3
At least two studies with level of evidence score 3 Three or more studies with level of evidence score 3
Effectiveness of the intervention
Number needed to genotype (NNG) 100 < NNG ≤ 1000
10 < NNG ≤ 100
NNG ≤ 10
PGx information in the drug-label
Recommendation to genotype
At least one genotype/phenotype mentioned as a contraindication
Total Score
Corresponding Clinical Implication Scoree
Possible score
+ ++ +
+ ++ +++
+ ++ +++
+ +
9+
Given score
++a
+++b
++c
+d
8+
Essential
a Patients assigned to be DPD deficient but have received normal doses of fluoropyrimidines been associated with CTCAE grade 5 toxicity;
b Eight studies of sufficient quality have shown an association with CTCAE grade 5 toxicity (references in Supplementary Table 1: 10, 15, 16, 18, 26, 29, 30 and 33);
c The NNG was calculated using the “Calculations of the number of adverse events prevented with an effective pre-emptive genotyping program”.1 The pooled odds ratios and relative risks for*2A, 1236A, 2846T and *13 was 5.2, extracted from meta-analyses Meulendijks et al., Terrazzino et al., and Rosmarin et al.2-4 The calculated NNG was 53.9;
d In the European Union, DPD deficiency is mentioned in the current version of the summary of product characteristics (SPC) of capecitabine in the sections Contraindications and Special Warnings and Precautions for Use.5 Similar information on DPD deficiency is provided in the United States by the Food and Drug Administration (FDA) for capecitabine.6 Comparable reports are made in SPCs of 5-FU;7,8
e essential, beneficial, potentially beneficial or not required.
Abbreviations: DPD: dihydropyrimidine dehydrogenase; CTCAE: Common terminology criteria for adverse events.
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