Page 161 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Safety analysis on DPYD genotype-guided dosing
activity was determined (Figure 3). Mean DPD activity (with standard deviation) in DPYD wild-type patients was 9.4 (3.6) nmol/(mg*h), similar to as previously published.23 For the c.1236G>A variant (N=35), the mean DPD activity was 7.5 (2.8) nmol/(mg*h) (i.e. a 20% reduction compared to wild-type). The mean DPD activity for c.2846A>T (N=12) was 6.2
(1.9) nmol/(mg*h) (34% reduction), and for DPYD*2A (N=8) 5.2 (0.6) nmol/(mg*h) (45% reduction). The single patient carrying c.1679T>G had a DPD enzyme activity of 3.8 nmol/ (mg*h) (60% reduction). For c.1236G>A, c.2846A>T, and DPYD*2A, the mean DPD enzyme activity was significantly lower than the mean for wild-type patients. Statistical analysis was
not possible for c.1679T>G. No correlation between DPD enzyme activity and the occurrence
of severe fluoropyrimidine-related toxicity in DPYD variant allele carrying patients was seen 5 (Figure 3 and Supplementary Table 4).
DPD activity in PBMCs per genotype
20 15 10
5 0
DPYD genotype
Figure 3. DPD enzyme activity in DPYD variant allele carriers and wild-type patients
Wild-type patients were wild-type for the four DPYD variants that were prospectively tested. Mean DPD enzyme activity was statistically significantly lower than wild-type (mean 9.4 (3.6) nmol/[mg*h]) for the DPYD variants as determined by a t-test: c.1236G>A (7.5 (2.8) nmol/[mg*h], p=0.0050), c.2846A>T (6.2 (1.9) nmol/[mg*h], p=0.0034), and DPYD*2A (5.2 (0.6) nmol/[mg*h], p=0.0012). As only one patient carried c.1679T>G, no statistical test could be performed for this variant. However, the single measurement in this patient was in the range of DPD deficiency (3.8 nmol/[mg*h]). Patients with grade ≥3 fluoropyrimidine-related toxicity are depicted by closed triangles, patients without grade <3 toxicity by open circles; wild-type patients are treated with standard fluoropyrimidine doses, DPYD variant allele carriers with initially reduced doses according to protocol.
Abbreviations: DPD: dihydropyrimidine dehydrogenase; PBMCs: peripheral blood mononuclear cells.
Discussion
This is, to our knowledge, the first prospective study to investigate the effect on fluoropyrimidine-related toxicity by dose individualization based on four DPYD variants. Our results demonstrate that genotype-guided dosing is feasible in clinical practice. Dose individualization markedly decreased the risk of severe toxicity for DPYD*2A carriers, was
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DPD enzyme activity (nmol/[mg*h])
Wild-type c.1236G>A
c.2846A>T DPYD*2A
c.1679T>G