Page 160 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
1.18─2.42), showing that the toxicity risk was still increased even when applying a 25% dose reduction. For c.2846A>T, the risk of severe toxicity determined in the meta-analysis was 3.11 (95%CI: 2.25─4.28),10 which was decreased to 2.00 (95%CI: 1.19─3.34) after 25% dose reduction. However, this risk was still higher compared to non-carriers of this variant. For the c.1679T>G variant no relative risk could be calculated, as only one patient with this variant was included.
Pharmacokinetics of DPYD-guided dosing
A total of 26 DPYD variant allele carriers (of which 16 c.1236G>A carriers, five c.2846A>T carriers, four DPYD*2A carriers and one c.1679T>G carrier) treated with a reduced fluoropyrimidine dose gave informed consent to draw blood for pharmacokinetic analysis. Mean AUC values of the DPYD variant allele carriers and control values are depicted in Figure 2. Mean exposure to capecitabine and all metabolites, including 5-FU, was comparable between patients dosed based on DPYD genotype and control values,20 suggesting that mean drug exposure of all combined DPYD variant allele carriers treated with a reduced dose was adequate. However, in line with toxicity data, AUC values for 5-FU were markedly higher for c.1236G>A carriers and especially for c.2846A>T carriers, compared to DPYD*2A and c.1679T>G carriers as shown in the Supplementary Table 3.
20,000 15,000 10,000
800 600 400
DPYD variant allele carriers Wild-type patients (control)
5,000 200 00
Metabolites
Figure 2. Pharmacokinetics of DPYD-guided capecitabine dosing
Depicted are the mean AUCs of capecitabine, and the metabolites 5’DFCR, 5’DFUR, 5-FU and FBAL of the DPYD variant allele carriers treated with DPYD-genotype guided dose (blue) and control values from wild-type patients from a published study (red).20 Error bars represent the standard deviation. 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; CAP: capecitabine; FBAL: fluoro- β-alanine.
DPD enzyme activity
In 56 DPYD variant allele carriers and 82 wild-type patients (participating in a subgroup of the study where DPD phenotyping tests were investigated), pretreatment DPD enzyme
158
AUC (ng*h/ml)
AUC (ng*h/ml)
CAP 5'DFCR
5'DFUR FBAL
5-FU
5-FU