Page 113 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Supplement
ref. 3
SPC Teysuno (tegafur/gimeracil/ oteracil) 05-04-17.
Level of evidence score: 0
gene act. 0: CTC-AE 4
gene act. 0,5- 1,5: E
they were heterozygous and did not have a second unknown non-functional allele.
The authors stated that tegafur-uracil is probably not safe in patients with partial DPD deficiency due to the greater effect of the DPD inhibitor uracil in these patients. They referred to an article that showed that uracil increases the half-life of fluorouracil to a greater extent in DPD-deficient patients, which leads to an increased risk of toxicity.
The authors also stated that the tegafur dose 4 in tegafur-gimeracil-oteracil is 3x as low as in
tegafur-uracil, while the DPD inhibitor is 200x more
potent. However, 5-FU is still metabolised by DPD
after administration of tegafur-gimeracil-oteracil. This means that DPD also remains essential for detoxification of 5-FU in this instance.
Contraindications:
Known dihydropyrimidine dehydrogenase (DPD) deficiency.
History of severe and unexpected reactions to fluoropyrimidine therapy.
Pharmacodynamics: Mean 5-FU maximum
plasma concentration (Cmax) and area under
the concentration-time curve (AUC) values
were approximately 3-fold higher after Teysuno administration than after administration of tegafur alone, despite a 16-fold lower Teysuno dose (50 mg of tegafur) compared to tegafur alone (800 mg),
and are attributed to inhibition of DPD by gimeracil. Maximum plasma uracil concentration was observed at 4 hours, with a return to baseline levels within approximately 48 hours after dosing, indicating the reversibility of DPD inhibition by gimeracil. In man, the apparent terminal elimination half-life (T1/2)
of 5-FU observed after administration of Teysuno (containing tegafur, a 5-FU prodrug) was longer (approximately 1.6-1.9 hours) than that previously reported after intravenous administration of 5-FU (10 to 20 minutes). Following a single dose of Teysuno, T1/2 values ranged from 6.7 to 11.3 hours for tegafur, from 3.1 to 4.1 hours for gimeracil and from 1.8 to 9.5 hours for oteracil.
Interactions: Sorivudine or its chemically related analogues such as brivudine irreversibly inhibit DPD, resulting in a significant increase in 5-FU exposure. This may lead to increased clinically significant fluoropyrimidine-related toxicities with potentially fatal outcomes.
Abbreviations: 5-FU: 5-fluorouracil; DPD: dihydropyrimidine dehydrogenase; gene act.: gene activity score; gene activity score 2: two fully functional alleles (extensive metaboliser); gene activity score 1.5: one fully functional and one partially functional allele; gene activity score 1: one fully functional and one non-functional allele or two partially functional alleles; gene activity score 0.5: one non-functional and one partially functional allele; gene activity score 0: two non-functional alleles.
111