Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Summary

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency. In addition to the genotyping, the DPD phenotype of all patients will be determined by measuring the baseline dihydrouracil/uracil (DHU/U) ratio, in order to investigate whether phenotype-guided treatment can further improve patient safety. In a subgroup of patients, other phenotyping methods will be tested: measuring the plasma levels of uracil after a uracil test dose and a uracil breath test after a dose of \[2-13C\] -labeled uracil. To validate these tests, these phenotyping results will be compared with the results of a DPD activity assay (which measures DPD enzyme activity in peripheral blood mononuclear cells), which is considered the gold standard in measuring DPD phenotype.

Timeline

Start

2015-03

Primary completion

2018-01

Completion

2018-03

Publications

• Knikman JE, Lopez-Yurda M, Meulendijks D, Deenen MJ, Schellens JHM, Beijnen J, Cats A, Guchelaar HJ. A Nomogram to Predict Severe Toxicity in DPYD Wild-Type Patients Treated With Capecitabine-Based Anticancer Regimens. Clin Pharmacol Ther. 2024 Feb;115(2):269-277. doi: 10.1002/cpt.3100. Epub 2023 Nov 29.
• Knikman JE, Wilting TA, Lopez-Yurda M, Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Nieboer P, Droogendijk HJ, Creemers GJ, Mandigers CMPW, Imholz ALT, Mathijssen RHJ, Portielje JEA, Valkenburg-van Iersel L, Vulink A, van der Poel MHW, Baars A, Swen JJ, Gelderblom H, Schellens JHM, Beijnen JH, Guchelaar HJ, Cats A. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis. J Clin Oncol. 2023 Dec 10;41(35):5411-5421. doi: 10.1200/JCO.22.02780. Epub 2023 Aug 28.
• Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers CMPW, Rosing H, Beijnen JH, Werkhoven EV, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 2018 Nov;19(11):1459-1467. doi: 10.1016/S1470-2045(18)30686-7. Epub 2018 Oct 19.
• Jacobs BA, Deenen MJ, Pluim D, van Hasselt JG, Krahenbuhl MD, van Geel RM, de Vries N, Rosing H, Meulendijks D, Burylo AM, Cats A, Beijnen JH, Huitema AD, Schellens JH. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. Br J Clin Pharmacol. 2016 Sep;82(3):706-16. doi: 10.1111/bcp.13007. Epub 2016 Jun 3.

Drugs

Indications