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7 results on '"dihydropyrimidine dehydrogenase"'

1. La dihydropyrimidine déshydrogénase (DPD).

Author

Gamelin, E., Boisdron-Celle, M., and Morel, A.

Subjects
*DIHYDROPYRIMIDINE dehydrogenase, *FLUOROPYRIMIDINES, *GAUSSIAN function, *GENETIC mutation, *MEDICAL care, *PUBLIC health, *PHENOTYPES
Abstract

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the catabolism of fluoropyrimidines. Its activity follows a Gaussian curve in the general population and some mutations have been identified in the gene reported to cause early severe related adverse events, in 2 to 5% of the patients. It is clearly a problem of public healthcare that cannot be underestimated. We review the performances of assays that assess DPD status. The combination of 2 complementary techniques, genotyping and enzyme phenotyping, suitable for routine clinical applications is crucial for reliably detecting DPD deficiency and avoiding early severe toxicity associated with fluoropyrimidines. [ABSTRACT FROM AUTHOR]

Published
2014
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2. [Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]

Author

Loriot, Marie-Anne, Masskouri, Fadil, Carni, Paolo, Le Malicot, Karine, Seitz, Jean-François, Michel, Pierre, Legoux, Jean-Louis, Bouche, Olivier, André, Thierry, Faroux, Roger, Delaloge, Suzette, Malka, David, Guigay, Joël, Thariat, Juliette, Thomas, Fabienne, Barin-Le-Guellec, Chantal, Ciccolini, Joseph, Boyer, Jean-Christophe, Etienne-Grimaldi, Marie-Christine, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Francophone de la Cancérologie Digestive, FFCD, Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), F2ME, PSA Peugeot - Citroën (PSA), PSA Peugeot Citroën (PSA)-PSA Peugeot Citroën (PSA)-Laboratoire Pluridisciplinaire de Recherche en Ingénierie des Systèmes, Mécanique et Energétique (PRISME), Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO), Regional Hospital of Orleans, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHD Vendée - Hôpital Les Oudairies [La Roche sur Yon], Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Medical Oncology Department [Nice], COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Laboratoire de biochimie et biologie moléculaire, Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Biomedical Research, Dihydropyrimidine Dehydrogenase Deficiency, MESH: Pharmacovigilance, [SDV]Life Sciences [q-bio], Surveys, MESH: Health Care Surveys, Digestive System Neoplasms, MESH: Genotype, Pharmacovigilance, MESH: Practice Guidelines as Topic, Antineoplastic Combined Chemotherapy Protocols, MESH: Otorhinolaryngologic Neoplasms, Oncologists, MESH: Antimetabolites, Antineoplastic, Enquête, DPD, MESH: Antineoplastic Combined Chemotherapy Protocols, Practice Guidelines as Topic, Screening, Female, Fluorouracil, France, Dihydropyrimidine dehydrogenase, Fluoropyrimidine, Antimetabolites, Antineoplastic, Genotype, Breast Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Dihydropyrimidine déshydrogénase, Reimbursement Mechanisms, Toxicité, MESH: Reimbursement Mechanisms, MESH: Biology, Humans, Biology, Capecitabine, MESH: Humans, Toxicity, MESH: Digestive System Neoplasms, MESH: Biomedical Research, MESH: Oncologists, MESH: Capecitabine, MESH: France, Otorhinolaryngologic Neoplasms, Pyrimidines, Dépistage, Health Care Surveys, MESH: Pyrimidines, MESH: Dihydropyrimidine Dehydrogenase Deficiency, MESH: Female, MESH: Fluorouracil, MESH: Breast Neoplasms
Abstract

International audience; Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

Published
2019

3. Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer

Author

Alexandre Evrard, Etienne Chatelut, Joseph Ciccolini, Marie-Noëlle Paludetto, Françoise Goirand, Manon Launay, Antonin Schmitt, Florian Lemaitre, Jean-Christophe Boyer, Romain Guilhaumou, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Claudius-Regaud [IUCT-O, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Marseille, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, medicine.medical_specialty, medicine.medical_treatment, 5-fluorouracile, [SDV.CAN]Life Sciences [q-bio]/Cancer, Therapeutic drug monitoring, 030226 pharmacology & pharmacy, 03 medical and health sciences, Suivi thérapeutique pharmacologique, 0302 clinical medicine, Pharmacokinetics, Toxicité, Dihydropyrimidine dehydrogenase, Medicine, Radiology, Nuclear Medicine and imaging, Digestive cancer, Gynecology, Recommandation, medicine.diagnostic_test, Toxicity, business.industry, Pharmacocinétique, Hematology, General Medicine, 3. Good health, Regimen, Oncology, 030220 oncology & carcinogenesis, Dose reduction, business, Adjuvant, Fluoropyrimidine
Abstract

International audience; Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.

Published
2018

4. 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

Author

Xavier Fonrose, Bernard Royer, Sylvie Quaranta, Anne-Sophie Wozny, Nicolas Picard, Vianney Poinsignon, Fadil Masskouri, Antonin Schmitt, Jean-Christophe Boyer, Franck Broly, Fabienne Thomas, Gérard Milano, Céline Narjoz, Claire Lafay-Chebassier, Joseph Ciccolini, Céline Verstuyft, Angelo Paci, Christine Bobin-Dubigeon, Alexandre Harlé, Marie-Christine Etienne-Grimaldi, Alexandre Evrard, Benjamin Hennart, Laurent Becquemont, Marie-Anne Loriot, Chantal Barin-Le-Guellec, CHU Lille, Institut Pasteur de Lille, Université de Lille, Toxicologie et Génopathies [CHRU Lille], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Simulation & Modelling : Adaptive Response for Therapeutics in Cancer (SMARTc unit), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Institut Claudius Regaud, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Département Micro-Ondes (MO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Service de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Toxicologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, UNICANCER-Université Côte d'Azur (UCA), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Individualisation des traitements des cancers ovariens (ITCO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, Institut Mines-Télécom [Paris] (IMT)-Télécom Bretagne-Université européenne de Bretagne - European University of Brittany (UEB), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Centre Antoine Lacassagne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre

Subjects
03 medical and health sciences, Cancer Research, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Radiology, Nuclear Medicine and imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, General Medicine, Fluoropyrimidine, 5-Fluorouracile, Capécitabine, Dihydropyrimidine déshydrogénase, DPYD, Dépistage, Toxicité, Recommandation, Pharmacogénétique, 030226 pharmacology & pharmacy, 5Fluorouracil, Capecitabine, Dihydropyrimidine dehydrogenase, Screening, Toxicity, Recommendation, Pharmacogenetics, 3. Good health
Abstract

Les fluoropyrimidines restent les molécules anticancéreuses les plus prescrites dans le traitement des tumeurs solides. Elles induisent des toxicités sévères chez 10–40 % des patients et des toxicités létales chez 0,2–0,8 % des patients. Une abondante littérature a établi le lien entre un déficit enzymatique en dihydropyrimidine déshydrogénase (DPD, enzyme qui dégrade le 5-FU) et la survenue d’une toxicité sévère sous fluoropyrimidine. Si les déficits complets en DPD sont rares (0,1–0,5 %), les déficits partiels sont retrouvés chez 3–15 % des patients. La recherche du déficit en DPD peut être réalisée par phénotypage (mesure directe ou indirecte de l’activité enzymatique) ou par génotypage (recherche des principaux polymorphismes fonctionnels du gène DPYD). Actuellement, il n’existe pas d’obligation réglementaire pour le dépistage du déficit en DPD avant l’administration de fluoropyrimidines. Sur la base des niveaux de preuve issus de la littérature, et des pratiques actuelles, le Groupe de Pharmacologie Clinique Oncologique (GPCO)-UNICANCER et le Réseau National de Pharmacogénétique hospitalière (RNPGx) recommandent : (1) de rechercher un déficit en DPD avant la mise en route de tout traitement à base de 5-FU ou capécitabine ; (2) de réaliser ce dépistage par phénotypage en dosant en première intention l’uracile plasmatique (U) (éventuellement complété par le rapport dihydrouracil/U) et en y associant le génotypage des variants *2A, *13, p.D949V et HapB3 ; (3) de réduire si nécessaire la posologie en fonction du statut DPD dès la première cure et d’envisager une augmentation de dose aux cures suivantes en fonction de la tolérance. Actuellement en France, 17 laboratoires hospitaliers réalisent en routine la recherche du déficit en DPD. Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency. 105;4

Published
2018

5. Pharmacologie comparée des fluoropyrimidines orales.

Author

Milano, G.

Subjects
*FLUOROPYRIMIDINES, *PHARMACODYNAMICS, *PRODRUGS, *BIOTRANSFORMATION (Metabolism), *PHARMACOKINETICS, *IMMUNOMODULATORS
Abstract

The main purpose of the present review article is to shed light on the different 5-FU prodrugs by underlining their respective pharmacological features in terms of metabolic activation, DPD inhibition, pharmacokinetic profile and possibilities of biomodulation. Oral fluoropyrimidines differ particularly in their pharmacokinetic profile and especially in the delivery of circulating 5-FU. There are now possibilities to achieve pharmacomodulation of oral fluoropyrimidines, notably for tegafur/uracil (UFT®) and capecitabine. These applications open up the prospect of establishing significant novel treatment protocols based on drug combinations. [ABSTRACT FROM AUTHOR]

Published
2004
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6. [Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists].

Author

Loriot MA, Masskouri F, Carni P, Le Malicot K, Seitz JF, Michel P, Legoux JL, Bouché O, André T, Faroux R, Delaloge S, Malka D, Guigay J, Thariat J, Thomas F, Barin-Le-Guellec C, Ciccolini J, Boyer JC, and Étienne-Grimaldi MC

Subjects
Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biology, Biomedical Research, Breast Neoplasms drug therapy, Capecitabine therapeutic use, Digestive System Neoplasms drug therapy, Dihydropyrimidine Dehydrogenase Deficiency genetics, Female, Fluorouracil therapeutic use, France, Genotype, Humans, Oncologists, Otorhinolaryngologic Neoplasms drug therapy, Pharmacovigilance, Practice Guidelines as Topic, Pyrimidines adverse effects, Pyrimidines therapeutic use, Reimbursement Mechanisms, Antimetabolites, Antineoplastic adverse effects, Capecitabine adverse effects, Dihydropyrimidine Dehydrogenase Deficiency diagnosis, Dihydropyrimidine Dehydrogenase Deficiency drug therapy, Fluorouracil adverse effects, Health Care Surveys statistics & numerical data
Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Published
2019
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7. [Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks].

Author

Loriot MA, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G, Picard N, Becquemont L, Verstuyft C, Narjoz C, Schmitt A, Bobin-Dubigeon C, Harle A, Paci A, Poinsignon V, Quaranta S, Evrard A, Hennart B, Broly F, Fonrose X, Lafay-Chebassier C, Wozny AS, Masskouri F, Boyer JC, and Etienne-Grimaldi MC

Subjects
Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Capecitabine administration & dosage, Capecitabine adverse effects, Dihydropyrimidine Dehydrogenase Deficiency diagnosis, Dihydrouracil Dehydrogenase (NADP) analysis, Dihydrouracil Dehydrogenase (NADP) genetics, Fluorouracil administration & dosage, Fluorouracil adverse effects, France, Humans, Neoplasms drug therapy, Phenotype, Practice Guidelines as Topic, Pyrimidines administration & dosage, Pyrimidines adverse effects, Pyrimidines therapeutic use, Uracil blood, Antimetabolites, Antineoplastic therapeutic use, Capecitabine therapeutic use, Dihydropyrimidine Dehydrogenase Deficiency complications, Fluorouracil therapeutic use
Abstract

Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Published
2018
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