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DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update.
Ann Oncol 2017; 28(12):2915-2922AO

Abstract

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

Authors+Show Affiliations

Division of Pharmacology. Department of Clinical Pharmacology, Division of Medical Oncology.Division of Pharmacology. Department of Clinical Pharmacology, Division of Medical Oncology.Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam. Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht.Department of Gastroenterology and Hepatology, Division of Medical Oncology.Division of Pharmacology. Department of Clinical Pharmacology, Division of Medical Oncology. Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29045513

Citation

Henricks, L M., et al. "DPYD Genotype-guided Dose Individualization to Improve Patient Safety of Fluoropyrimidine Therapy: Call for a Drug Label Update." Annals of Oncology : Official Journal of the European Society for Medical Oncology, vol. 28, no. 12, 2017, pp. 2915-2922.
Henricks LM, Opdam FL, Beijnen JH, et al. DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update. Ann Oncol. 2017;28(12):2915-2922.
Henricks, L. M., Opdam, F. L., Beijnen, J. H., Cats, A., & Schellens, J. H. M. (2017). DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update. Annals of Oncology : Official Journal of the European Society for Medical Oncology, 28(12), pp. 2915-2922. doi:10.1093/annonc/mdx411.
Henricks LM, et al. DPYD Genotype-guided Dose Individualization to Improve Patient Safety of Fluoropyrimidine Therapy: Call for a Drug Label Update. Ann Oncol. 2017 Dec 1;28(12):2915-2922. PubMed PMID: 29045513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update. AU - Henricks,L M, AU - Opdam,F L, AU - Beijnen,J H, AU - Cats,A, AU - Schellens,J H M, PY - 2017/10/19/pubmed PY - 2017/10/19/medline PY - 2017/10/19/entrez KW - DPYD KW - capecitabine KW - dihydropyrimidine dehydrogenase KW - fluoropyrimidines KW - fluorouracil KW - pharmacogenetics SP - 2915 EP - 2922 JF - Annals of oncology : official journal of the European Society for Medical Oncology JO - Ann. Oncol. VL - 28 IS - 12 N2 - The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care. SN - 1569-8041 UR - https://www.unboundmedicine.com/medline/citation/29045513/DPYD_genotype_guided_dose_individualization_to_improve_patient_safety_of_fluoropyrimidine_therapy:_call_for_a_drug_label_update_ L2 - https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdx411 DB - PRIME DP - Unbound Medicine ER -