Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study.

Abstract

In clinical practice, 25-30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype-based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency. Although the evidence for genotype-directed dosing of fluoropyrimidines is substantial, the level of evidence supporting plasma uracil levels to predict DPD activity in clinical practice is limited. Notwithstanding this, uracil-based phenotyping is now used in clinical practice in various countries in Europe. We aimed to determine the value of pretreatment uracil levels in predicting DPD deficiency and severe treatment-related toxicity. To this end, we determined pretreatment uracil levels in 955 patients with cancer, and assessed the correlation with DPD activity in peripheral blood mononuclear cells (PBMCs) and fluoropyrimidine-related severe toxicity. We identified substantial issues concerning the use of pretreatment uracil in clinical practice, including large between-center study differences in measured pretreatment uracil levels, most likely as a result of pre-analytical factors. Importantly, we were not able to correlate pretreatment uracil levels with DPD activity nor were uracil levels predictive of severe treatment-related toxicity. We urge that robust clinical validation should first be performed before pretreatment plasma uracil levels are used in clinical practice as part of a dosing strategy for fluoropyrimidines.

• Authors: Mirjam de With, Jonathan Knikman, Femke M de Man, Carin A T C Lunenburg, Linda M Henricks, André B P van Kuilenburg, Jan G Maring, Maurice C van Staveren, Niels de Vries, Hilde Rosing, Jos H Beijnen, Dick Pluim, Anil Modak, Alex L T Imholz, Ron H N van Schaik, Jan H M Schellens, Hans Gelderblom, Annemieke Cats, Henk-Jan Guchelaar, Ron H J Mathijssen, Jesse J Swen, Didier Meulendijks
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 112 Issue 1 Pg. 62-68 (07 2022) ISSN: 1532-6535 [Electronic] United States
• PMID: 35397172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Antimetabolites, Antineoplastic
• Uracil
• Dihydrouracil Dehydrogenase (NADP)

Topics

• Antimetabolites, Antineoplastic
• Dihydropyrimidine Dehydrogenase Deficiency (drug therapy, genetics)
• Dihydrouracil Dehydrogenase (NADP) (genetics, metabolism)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Prospective Studies
• Uracil (blood)