Page 173 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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Supplementary Table 3. Pharmacokinetic parameters of capecitabine and metabolites in DPYD variant allele carriers and controls
Metabolite
Mean AUC0-∞ (ng*h/ml) [CV%]a DPYD variant allele carriers
Wild-type control patients (N=23)b
Mean T1/2 (h) [CV%]
DPYD variant allele carriers
Wild-type control patients (N=23)b
Capecitabine 5’DFCR 5’DFUR
5-FU
(N=26)
6007 [60%]
7792 [56%]
8243 [45%]
398 [77%]
14295 [41%]
Mean AUC0-∞ (ng*h/ml) [CV%]a
4281 [31%] 8192 [30%] 7673 [29%] 381 [40%] 14177 [31%]
(N=26)
0.73 [49%]
0.83 [43%]
0.85 [38%]
0.92 [112%]
2.2 [133%]
Mean T1/2 (h) [CV%]
0.76 [55%] 1.0 [45%] 0.9 [34%] 1.0 [57%] 2.6 [33%]
FBAL
Metabolite
c.1236G>A (N=16)
c.2846A>T (N=5)
DPYD*2A (N=4)
c.1679T>G (N=1)
c.1236G>A (N=16)
c.2846A>T (N=5)
DPYD*2A (N=4)
c.1679T>G (N=1)
Capecitabine 5’DFCR 5’DFUR
5-FU
6579 [65%] 9162 [45%] 9319 [41%] 346 [49%] 16217 [30%]
5944 [26%] 8320 [50%] 8150 [46%] 765 [64%] 15627 [36%]
4460 [51%] 2552 [25%] 4824 [17%] 197 [54%] 6244 [18%]
3350
4185
5161
219
9082
0.77 [48%] 0.84 [51%] 0.84 [38%] 1.1 [120%] 2.9 [78%]
0.68 [50%] 0.88 [28%] 0.73 [41%] 0.75 [47%] 2.5 [14%]
0.66 [61%] 0.83 [21%] 0.84 [19%] 0.54 [20%] 2.2 [15%]
0.53 0.51 1.6 0.82 2.9
FBAL
a Note that for all metabolites the AUC is calculated until infinity (AUC0-∞, extrapolated from the last time point). Only for FBAL,
the longest half-life, this resulted in a difference between the AUC until last time point (AUC0-t) and AUC0-∞, with the AUC0-∞ being on average 26% higher than AUC0-t. For the metabolites capecitabine, 5’DFCR, 5’DFUR and 5-FU the difference between AUC0-t and AUC0-∞ was respectively 0.5%, 0.8%, 1%, and 4%;
b Control values are derived from Deenen et al.4 for patients with advanced cancer of the stomach or gastroesophageal junction after administration of capecitabine 850 mg/m2 (dose level 2 of the study).
Abbreviations: 5’DFCR: 5’-deoxy-5-fluorocytidine; 5’DFUR: 5’-deoxy-5-fluorouridine; 5-FU: 5-fluorouracil; AUC: area under the plasma concentration-time curve; CV%: coefficient of variation; FBAL: fluoro-β-alanine; T1/2: half-life.
the metabolite with