Evaluation of an oral uracil loading test to identify DPD-deficient patients using a limited sampling strategy
Maurice C. van Staveren,André B.P. van Kuilenburg,Henk-Jan Guchelaar,Judith Meijer,Cornelis J. A. Punt,Robert S. de Jong,Hans Gelderblom,J. G. Maring +7 more
TLDR
The high sensitivity of the U/DHU ratio at t = 120 min for detecting DPD deficiency, as defined by D PD activity in PBMCs, showed that the oral U loading dose can effectively identify patients with reduced DPD activity.Abstract:
AIM Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity following 5-fluorouracil (5FU) or capecitabine (CAP) treatment Uracil (U) can be used as a probe to determine systemic DPD activity The present study was performed to assess the sensitivity and specificity of a U loading dose for detecting DPD deficiency METHODS Cancer patients with Common Toxicity Score (CTC) grade III or IV toxicity after the first or second cycle of 5-FU or CAP treatment were asked to participate Based on DPD activity in PBMCs, patients were divided into two groups: DPD activity in peripheral blood mononuclear cells (PBMCs) <5 nmol mg(-1) *h(-1) (deficient group) and ≥ 5 nmol mg(-1) *h(-1) U 500 mg m(-2) was administered orally and plasma concentrations of U and dihydrouracil (DHU) were determined In the deficient group, polymerase chain reaction amplification of all 23 coding exons and flanking intronic regions of DPYD was performed A U pharmacokinetic model was developed and used to determine the maximum enzymatic conversion capacity (Vmax ) of the DPD enzyme for each patient The sensitivity and specificity of Vmax, U concentration and the U/DHU concentration ratio were determined RESULTS A total of 47 patients were included (19 DPD deficient, 28 DPD normal) Of the pharmacokinetic parameters investigated, a sensitivity and specificity of 80% and 98%, respectively, was obtained for the U/DHU ratio at t = 120 min CONCLUSIONS The high sensitivity of the U/DHU ratio at t = 120 min 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 activityread more
Citations
More filters
Journal ArticleDOI
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update
Ursula Amstutz,Linda M. Henricks,Steven M. Offer,Julia M. Barbarino,Jan H.M. Schellens,Jesse J. Swen,Teri E. Klein,Howard L. McLeod,Kelly E. Caudle,Robert B. Diasio,Matthias Schwab +10 more
TL;DR: The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine).
Journal ArticleDOI
Therapeutic drug monitoring of 5-fluorouracil
TL;DR: Dose adjustment of 5-FU is feasible, and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy, there is growing evidence to show.
Journal ArticleDOI
New advances in DPYD genotype and risk of severe toxicity under capecitabine.
Marie-Christine Etienne-Grimaldi,Jean-Christophe Boyer,Christophe Béroud,Litaty Mbatchi,André B.P. van Kuilenburg,Christine Bobin-Dubigeon,Fabienne Thomas,Etienne Chatelut,Jean-Louis Merlin,Frédéric Pinguet,Christophe Ferrand,Judith L Meijer,Alexandre Evrard,Laurence Llorca,Gilles Romieu,Philippe Follana,Thomas Bachelot,Loic Chaigneau,Xavier Pivot,Véronique Diéras,Rémy Largillier,Mireille Mousseau,Anthony Gonçalves,Henri Roché,Jacques Bonneterre,V. Servent,N. Dohollou,Yann Château,Emmanuel Chamorey,Jean-Pierre Desvignes,David Salgado,Jean-Marc Ferrero,Gérard Milano +32 more
TL;DR: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3–4 and grade 4 toxicities related to capecitabine, as compared to conventional genotypes restricted to consensual variants *2A, *13 and D949V.
Journal ArticleDOI
Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5-Fluorouracil Therapy.
Jan H. Beumer,Edward Chu,Carmen J. Allegra,Yusuke Tanigawara,Gérard Milano,Robert B. Diasio,Tae Won Kim,Ron H.J. Mathijssen,Li Zhang,Dirk Arnold,Katsuki Muneoka,Narikazu Boku,Markus Joerger +12 more
TL;DR: This systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology and strongly recommend TDM for the management of 5‐FU therapy in patients with colorectal or head‐and‐neck cancer receiving common 5-FU regimens.
Journal ArticleDOI
Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx
Marie-Anne Loriot,Joseph Ciccolini,Fabienne Thomas,Chantal Barin-Le-Guellec,Bernard Royer,Gérard Milano,Nicolas Picard,Laurent Becquemont,Céline Verstuyft,Céline Narjoz,Antonin Schmitt,Christine Bobin-Dubigeon,Alexandre Harlé,Angelo Paci,Vianney Poinsignon,Sylvie Quaranta,Alexandre Evrard,Benjamin Hennart,Franck Broly,Xavier Fonrose,Claire Lafay-Chebassier,Anne-Sophie Wozny,Fadil Masskouri,Jean-Christophe Boyer,Marie-Christine Etienne-Grimaldi +24 more
TL;DR: La recherche du deficit en DPD peut etre realisee par phenotypage (mesure directe ou indirecte de l’activite enzymatique) ou par genotypesage (recherche des principaux polymorphismes fonctionnels du gene DPYD).
References
More filters
Journal ArticleDOI
Pharmacogenetics: from bench to byte--an update of guidelines.
Jesse J. Swen,Marga Nijenhuis,A. de Boer,L. Grandia,A.H. Maitland-van der Zee,Hans Mulder,Gerard A. Rongen,R.H.N. van Schaik,Tom Schalekamp,Daan J Touw,J. van der Weide,Bob Wilffert,V.H.M. Deneer,Henk-Jan Guchelaar +13 more
TL;DR: Recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP3A5, and HLA‐B*5701, and factor V Leiden (FVL).
Journal ArticleDOI
Clinical pharmacology of 5-fluorouracil.
Robert B. Diasio,Barry E. Harris +1 more
TL;DR: 5-Fluorouracil, first introduced as a rationally synthesised anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin.
Journal Article
Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion
TL;DR: With the recent advent of programmable pumps, information on the circadian pattern of FUra and/or DPD may be useful in planning continuous infusion schedules in order that optimal plasma drug concentration may be maintained over a 24-h cycle, thereby enhancing the therapeutic efficacy of F Ura administered by continuous infusion.
Journal ArticleDOI
Population study of dihydropyrimidine dehydrogenase in cancer patients.
Marie-Christine Etienne,Jean-Léon Lagrange,Olivier Dassonville,Ronald A. Fleming,Antoine Thyss,Nicole Renée,M Schneider,F Demard,Gérard Milano +8 more
TL;DR: In this article, a prospective study on a large set of cancer patients in an attempt to evaluate the incidence of complete or partial dihydropyrimidine dehydrogenase deficiency as found in peripheral mononuclear cells (PMNC) was conducted.
Journal Article
Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene.
A. B. P. Van Kuilenburg,Janet Haasjes,Dick J. Richel,Lida Zoetekouw,G.H. van Lenthe,R.A. de Abreu,J. G. Maring,Peter Vreken,A. H. van Gennip +8 more
TL;DR: This study demonstrated that in 59% of the cases, a decreased DPD activity could be detected in peripheral blood mononuclear cells and demonstrated that at least 57% (8 of 14) of the patients with a reduced D PD activity have a molecular basis for their deficient phenotype.
Related Papers (5)
Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data
Didier Meulendijks,Linda M. Henricks,Gabe S. Sonke,Maarten J. Deenen,Tanja K. Froehlich,Ursula Amstutz,Carlo R. Largiadèr,Barbara A. Jennings,Anthony M. Marinaki,Jeremy D. Sanderson,Zdenek Kleibl,Petra Kleiblova,Matthias Schwab,Ulrich M. Zanger,Ulrich M. Zanger,Claire Palles,Ian Tomlinson,Eva Gross,André B.P. van Kuilenburg,Cornelis J. A. Punt,Miriam Koopman,Jos H. Beijnen,Jos H. Beijnen,Annemieke Cats,Jan H.M. Schellens,Jan H.M. Schellens +25 more