Capecitabine‐based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency. Issue 2 (30th September 2017)

• Record Type: Journal Article
• Authors: Henricks, Linda M.; Siemerink, Ester J.M.; Rosing, Hilde; Meijer, Judith; Goorden, Susan M.I.; Polstra, Abeltje M.; Zoetekouw, Lida; Cats, Annemieke; Schellens, Jan H.M.; van Kuilenburg, André B.P.
• Is Part Of: International journal of cancer. Volume 142:Issue 2(2018)
• Page Start: 424
• Page End: 430
• Publication Date: 2017-09-30
• Subjects: dihydropyrimidine dehydrogenase -- DPYD -- pharmacogenetics -- fluoropyrimidines -- capecitabine; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31065
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Fluoropyrimidines are frequently used anti‐cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine‐related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine‐treatment has generally been discouraged. During routine pretreatment screening, we identified a 59‐year‐old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD *2A. Despite absence of DPD activity, the patient was treated with capecitabine‐based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration‐time curve (AUC) and half‐life of 5‐fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m 2 . When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5‐fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine‐related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically‐guided dose administration, enables save fluoropyrimidine‐treatment with adequate drug exposure in completely DPD deficient patients. Abstract : What's new? Patients with reduced activity of dihydropyrimidine dehydrogenase (DPD) are at increased risk of developing severe fluoropyrimidine drug‐related toxicity. Here, the authors describe a case where a patient was identified with a complete DPD deficiency caused by a novel DPYD genotype, i.e. amplification of exons 17 and 18 in combination with DPYD *2A. Pharmacokinetic analyses showed that the chosen dose reduction of capecitabine to 150 mg per 5 days resulted in adequate drug exposure. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically‐guided dose administration, enables the safe treatment of completely DPD deficient patients with fluoropyrimidines.