In clinical practice, 25-30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available... Show moreIn 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. Show less
Fluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as... Show moreFluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as prolonged infusion. Many tissues throughout the body express thymidine phosphorylase. Dihydropyrimidine Dehydrogenase (DPD) is involved in the degradation of endogenous pyrimidine nucleosides, but also in the degradation of fluoropyrimidines. More than 80% of the amount of 5-FU administered is catabolized primarily in the liver where DPD is abundantly expressed. DPD is encoded by the DPYD gene for which 567 coding variants are known to date, some of them being pathogenic by reducing enzyme capacity. Interindividual variability in the activity of DPD influences 5-FU pharmacokinetics and a reduced DPD activity can lead to severe toxicity and even death following administration of 5-FU or capecitabine. Knowledge regarding the clinical impact of reduced DPD activity on the pharmacokinetics and pharmacodynamics of fluoropyrimidines may be useful to dose individualize therapy. In this thesis, an in depth overview is given of methods and their potential to optimize fluoropyrimidine dosing based on individual DPD enzyme activity. Furthermore an oral uracil loading dose as probe for DPD deficiency in cancer patients treated with fluoropyrimdines for this purpose is studied. Show less
Aim: Fluoropyrimidines are commonly used anti-cancer drugs, but lead to severe toxicity in 10-30% of patients. Prospective DPYD screening identifies patients at risk for toxicity and leads to a... Show moreAim: Fluoropyrimidines are commonly used anti-cancer drugs, but lead to severe toxicity in 10-30% of patients. Prospective DPYD screening identifies patients at risk for toxicity and leads to a safer treatment with fluoropyrimidines. This study evaluated the routinely application of prospective DPYD screening at the Leiden University Medical Center. Methods: Prospective DPYD screening as part of routine patient care was evaluated by retrospectively screening databases and patient files to determine genotype, treatment, dose recommendations and dose adjustments. Results: 86.9% of all patients with a first fluoropyrimidine prescription were screened. Fourteen out of 275 patients (5.1%) carried a DPYD variant and received a 25-50% dose reduction recommendation. None of the patients with a DPYD variant treated with a reduced dose developed toxicities. Conclusion: Prospective DPYD screening can be implemented successfully in a real world clinical setting, is well accepted by physicians and results in low toxicity. Show less
ConclusionsThe high sensitivity of the U/DHU ratio at t=120min for detecting DPD deficiency, as defined by DPD activity in PBMCs, showed that the oral U loading dose can effectively identify... Show moreConclusionsThe high sensitivity of the U/DHU ratio at t=120min for detecting DPD deficiency, as defined by DPD activity in PBMCs, showed that the oral U loading dose can effectively identify patients with reduced DPD activity. Show less
