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2. Population Modeling of Tumor Growth Curves, the Reduced Gompertz Model and Prediction of the Age of a Tumor

Author

Vaghi, Cristina, Rodallec, Anne, Fanciullino, Raphaelle, Ciccolini, Joseph, Mochel, Jonathan, Mastri, Michalis, Ebos, John M. L., Poignard, Clair, Benzekry, Sebastien, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Bebis, George, editor, Benos, Takis, editor, Chen, Ken, editor, Jahn, Katharina, editor, and Lima, Ernesto, editor

Published
2019
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7. Conditional generation of free radicals by selective activation of alkoxyamines: towards more effective and less toxic targeting of brain tumors

Author

Piris, Patricia, primary, Buric, Duje, additional, Yamasaki, Toshihide, additional, Huchedé, Paul, additional, Rossi, Maïlys, additional, Matteudi, Mélanie, additional, Montero, Marie-Pierre, additional, Rodallec, Anne, additional, Appay, Romain, additional, Roux, Christine, additional, Combes, Sébastien, additional, Pasquier, Eddy, additional, Castets, Marie, additional, André, Nicolas, additional, Brémond, Paul, additional, and Carré, Manon, additional

Published
2023
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11. Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques

Author

Guedj, Jérémie, Piorkowski, Géraldine, Jacquot, Frédéric, Madelain, Vincent, Nguyen, Thi Huyen Tram, Rodallec, Anne, Gunther, Stephan, Carbonnelle, Caroline, Mentré, France, Raoul, Hervé, and de Lamballerie, Xavier

Subjects
Ebola virus infections -- Drug therapy -- Patient outcomes -- Research, Antiviral agents -- Dosage and administration -- Research, Treatment outcome -- Analysis -- Research -- Health aspects, Ebola virus -- Analysis -- Health aspects -- Research, Biological sciences
Abstract

Background Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs). Methods and findings A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 [mu]g/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 [mu]g/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present. Conclusions Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions., Author(s): Jérémie Guedj 1,*, Géraldine Piorkowski 2, Frédéric Jacquot 3, Vincent Madelain 1, Thi Huyen Tram Nguyen 1, Anne Rodallec 2,4, Stephan Gunther 5, Caroline Carbonnelle 3, France Mentré 1, [...]

Published
2018
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12. Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer

Author

Sicard, Guillaume, Paris, Clément, Giacometti, Sarah, Rodallec, Anne, Ciccolini, Joseph, Rocchi, Palma, Fanciullino, Raphaëlle, 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), 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), Rocchi, Palma, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes

Subjects
lcsh:Pharmacy and materia medica, liposomes, [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, immunoliposomes, lcsh:RS1-441, [CHIM]Chemical Sciences, antisense oligonucleotides, prostate cancer, Article
Abstract

Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option&mdash, however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy.

Published
2020

16. Improving the efficacy of anti-cancer nanoparticles with data-driven mathematical modeling

Author

Vaghi, Cristina, Rodallec, Anne, Fanciullino, Raphaelle, Ciccolini, Joseph, Poignard, Clair, Benzekry, Sébastien, Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-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), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), 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)-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), and Benzekry, Sebastien

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, [STAT.AP]Statistics [stat]/Applications [stat.AP], [SPI] Engineering Sciences [physics], [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SPI]Engineering Sciences [physics], [SDV.CAN] Life Sciences [q-bio]/Cancer, [STAT.AP] Statistics [stat]/Applications [stat.AP], [SDV.IB]Life Sciences [q-bio]/Bioengineering, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

17. Abstract 3000: Impact of trastuzumab coating when prototyping immunoliposomes in breast cancer models: The more the merrier

Author

Rodallec, Anne, primary, Franco, Corentin, additional, Robert, Stéphane, additional, Sicard, Guillaume, additional, Giacometti, Sarah, additional, Savina, Ariel, additional, Bouquet, Fanny, additional, Lacarelle, Bruno, additional, Ciccolini, Joseph, additional, Poncelet, Philippe, additional, and Fanciullino, Raphaelle, additional

Published
2019
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19. From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Author

Rodallec,Anne, Sicard,Guillaume, Giacometti,Sarah, Carré,Manon, Pourroy,Bertrand, Bouquet,Fanny, Savina,Ariel, Lacarelle,Bruno, Ciccolini,Joseph, Fanciullino,Raphaelle, Rodallec,Anne, Sicard,Guillaume, Giacometti,Sarah, Carré,Manon, Pourroy,Bertrand, Bouquet,Fanny, Savina,Ariel, Lacarelle,Bruno, Ciccolini,Joseph, and Fanciullino,Raphaelle

Abstract

Anne Rodallec,1 Guillaume Sicard,1 Sarah Giacometti,1 Manon Carré,1 Bertrand Pourroy,2 Fanny Bouquet,3 Ariel Savina,3 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino1 1SMARTc Unit, Laboratory of Pharmacokinetics and Toxicology UFR Pharmacy, Center for Research on Cancer of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University, Marseille, France; 2Pharmacy Department, APHM La Conception, Marseille, France; 3Roche Institute, Boulogne Billancourt, France Purpose: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Materials and methods: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. Results: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231

Published
2018

20. Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer

Author

Rodallec,Anne, Brunel,Jean-Michel, Giacometti,Sarah, Maccario,Helene, Correard,Florian, Mas,Eric, Orneto,Caroline, Savina,Ariel, Bouquet,Fanny, Lacarelle,Bruno, Ciccolini,Joseph, Fanciullino,Raphaelle, Rodallec,Anne, Brunel,Jean-Michel, Giacometti,Sarah, Maccario,Helene, Correard,Florian, Mas,Eric, Orneto,Caroline, Savina,Ariel, Bouquet,Fanny, Lacarelle,Bruno, Ciccolini,Joseph, and Fanciullino,Raphaelle

Abstract

Anne Rodallec,1 Jean-Michel Brunel,2 Sarah Giacometti,1 Helene Maccario,3 Florian Correard,3 Eric Mas,3 Caroline Orneto,4 Ariel Savina,5 Fanny Bouquet,5 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino11SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR U1068 CNRS UMR 7258 Aix Marseille Université, Marseille, France; 2CRCM CNRS UMR 7258 Aix Marseille Université, Marseille, France; 3CRO2 UMR S_911 Aix Marseille Université, Marseille, France; 4Biopharmacy Laboratory, Aix Marseille Université, Marseille, France; 5Institut Roche, Boulogne Billancourt Cedex, FranceBackground: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab.Methods: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy.Results: ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard tre

Published
2018

21. From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer [Erratum]

Author

Rodallec,Anne, Sicard,Guillaume, Giacometti,Sarah, Carré,Manon, Pourroy,Bertrand, Bouquet,Fanny, Savina,Ariel, Lacarelle,Bruno, Ciccolini,Joseph, Fanciullino,Raphaelle, Rodallec,Anne, Sicard,Guillaume, Giacometti,Sarah, Carré,Manon, Pourroy,Bertrand, Bouquet,Fanny, Savina,Ariel, Lacarelle,Bruno, Ciccolini,Joseph, and Fanciullino,Raphaelle

Abstract

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer [Erratum]Rodallec A, Sicard G, Giacometti S, et al. Int J Nano. 2018;13: 6677–6688.On page 6684, Table 1 should be as follows:Read the original article

Published
2018

22. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

Author

Nguyen, Thi Huyen Tram, Guedj, Jérémie, Anglaret, Xavier, Laouénan, Cédric, Madelain, Vincent, Taburet, Anne-Marie, Baize, Sylvain, Sissoko, Daouda, Pastorino, Boris, Rodallec, Anne, Piorkowski, Géraldine, Carazo, Sara, Conde, Mamoudou N, Gala, Jean-Luc, Bore, Joseph Akoi, Carbonnelle, Caroline, Jacquot, Frédéric, Raoul, Hervé, Malvy, Denis, de Lamballerie, Xavier, Mentré, France, JIKI study group, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Programme PAC-CI, ANRS France Recherche Nord & sud Sida-hiv hépatites, Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Emergence des Pathologies Virales (EPV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Médecins Sans Frontières Belgique, The Alliance for International Medical Action [Dakar, Sénégal] (ONG ALIMA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Laboratoire des Fièvres Hémorragiques en Guinée, Université Gamal Abdel Nasser de Conakry, Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), The JIKI trial was supported by grants from the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France, http://www.anrs.fr/), the French Institute for Health Research (Inserm, Paris, France, http://www.inserm.fr/) and the European Commission (EU Horizon 2020 programme, grant N° 666092 - REACTION, http://ec.europa.eu/programmes/horizon2020/)., European Project: 666092,H2020,H2020-Adhoc-2014-20,REACTION(2014), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], MATEO, MATHIEU, Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans - REACTION - - H20202014-11-01 - 2016-10-31 - 666092 - VALID, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de génétique médicale UCL, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), and Université Catholique de Louvain (UCL)

Subjects
Male, Physiology, Blood plasma, Biochemistry, MESH: Child, Medicine and Health Sciences, Viral load, Child, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Aged, MESH: Guinea, MESH: Middle Aged, Pharmaceutics, lcsh:Public aspects of medicine, Hematology, Middle Aged, Ebolavirus, MESH: Amides, Body Fluids, Blood, MESH: Young Adult, Child, Preschool, Pyrazines, Creatinine, MESH: Pyrazines, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Drug therapy, Anatomy, Research Article, Adult, MESH: Antiviral Agents, lcsh:Arctic medicine. Tropical medicine, Adolescent, lcsh:RC955-962, Antiviral Agents, Microbiology, Young Adult, Virology, Albumins, Dose prediction methods, Humans, Pharmacokinetics, MESH: Ebolavirus, Aged, Pharmacology, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Biology and Life Sciences, Proteins, lcsh:RA1-1270, MESH: Adult, Hemorrhagic Fever, Ebola, Amides, MESH: Male, MESH: Hemorrhagic Fever, Ebola, Guinea, MESH: Female, Biomarkers, Viral Transmission and Infection
Abstract

Background In 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. Methods and findings Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p, Author summary In 2014–2015, the JIKI trial was conducted in Guinea to test favipiravir tolerance and efficacy in patients with Ebola virus disease (EDV). The main results of the trial were previously published without drug concentrations which were not available at the time of publication. The purpose of this study was to report favipiravir concentrations achieved in participants in the JIKI trial and to compare them with the targeted concentrations. We analyzed drug concentrations obtained at Day-2 and Day-4 and compared them to the targeted concentrations. At Day-2, favipiravir concentrations were significantly below but still close to the targeted concentration. At Day-4, a significant and unanticipated drop of concentrations as compared to Day-2 was observed. The origin of the lower-than-targeted concentrations and the unexpected drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. No significant correlation was found between the drug exposure and the virological response, indicating that it is possible that the favipiravir concentrations in the JIKI trial were not sufficient to strongly inhibit the viral replication. These findings suggest the necessity of performing dose-ranging studies with high doses of favipiravir in healthy volunteers to inform any further development of favipiravir for treatment of EVD.

Published
2017

25. Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer

Author

Rodallec, Anne, primary, Brunel, Jean-Michel, additional, Giacometti, Sarah, additional, Maccario, Helene, additional, Correard, Florian, additional, Mas, Eric, additional, Orneto, Caroline, additional, Savina, Ariel, additional, Bouquet, Fanny, additional, Lacarelle, Bruno, additional, Ciccolini, Joseph, additional, and Fanciullino, Raphaelle, additional

Published
2018
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29. Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase‐driven adaptive dosing of 5‐FU in patients with digestive cancer

Author

Launay, Manon, Dahan, Laetitia, Duval, Manon, Rodallec, Anne, Milano, Gérard, Duluc, Muriel, Lacarelle, Bruno, Ciccolini, Joseph, and Seitz, Jean‐Francois

Subjects
Adult, Aged, 80 and over, Male, Antimetabolites, Antineoplastic, Dihydropyrimidine Dehydrogenase Deficiency, Pharmacogenetics, Humans, Female, Fluorouracil, Middle Aged, Digestive System Neoplasms, Dihydrouracil Dehydrogenase (NADP), Aged
Abstract

5-FU is the backbone of most regimens in digestive oncology. Administration of standard 5-FU leads to 15-30% of severe side effects, and lethal toxicities are regularly reported with fluoropyrimidine drugs. Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome responsible for most cases of life-threatening toxicities upon 5-FU intake, and pre-treatment checking for DPD status should help to reduce both incidence and severity of side effects through adaptive dosing strategies.We have used a simple method for rapidly establishing the DPD phenotype of patients with cancer and used it prospectively in 59 routine patients treated with 5-FU-based therapy for digestive cancers. No patient with total DPD deficiency was found but 23% of patients exhibited poor metabolizer phenotype, and one patient was phenotyped as profoundly deficient. Consequently, 5-FU doses in poor metabolizer patients were cut by an average 35% as compared with non deficient patients (2390 ± 1225 mg vs. 3653 ± 1371 mg, P0.003, t-test).Despite this marked reduction in 5-FU dosing, similar efficacy was achieved in the two subsets (clinical benefit: 40 vs. 43%, stable disease: 40 vs. 37%, progressive disease: 20% in both subsets, P = 0.893, Pearson's chi-square). No difference in toxicities was observed (P = 0.104, Fisher's exact test). Overall, only 3% of early severe toxicities were recorded, a value markedly lower than the 15-30% ones usually reported with 5-FU.This feasibility study shows how simplified DPD-based adaptive dosing of 5-FU can reduce sharply the incidence of treatment-related severe toxicities while maintaining efficacy as part of routine clinical practice in digestive oncology.

Published
2015

31. Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer.

Author

Sicard G, Paris C, Giacometti S, Rodallec A, Ciccolini J, Rocchi P, and Fanciullino R

Abstract

Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option-however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy.

Published
2020
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32. Is There Any Room for Pharmacometrics With Immuno-Oncology Drugs? Input from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology.

Author

Rodallec A, Fanciullino R, Benzekry S, and Ciccolini J

Subjects
Animals, Antineoplastic Agents, Immunological therapeutic use, Humans, Immunotherapy, Neoplasms drug therapy, Neoplasms metabolism, Pharmacology, Clinical methods, Antineoplastic Agents, Immunological pharmacokinetics
Abstract

As part of the Pharmacology & Molecular Mechanisms (PAMM) Group, European Organization for Research and Treatment on Cancer (EORTC) 2019 winter Meeting Educational sessions, special focus has been placed on strategies to be undertaken to reduce the attrition rate when developing immune-oncology drugs. Immune checkpoint inhibitors have been game-changing drugs in several settings over the past decade such as melanoma and lung cancer. However, during the last years a rising number of studies failing to further improve clinical outcome in patients with cancer was recorded. Extensive pharmacometrics such as pharmacokinetics/pharmacodynamics modeling support should help to overcome the current glass ceiling that has apparently been reached with immuno-oncology drugs (IOD). In particular, it should help in the issue of setting up combinatorial regimen (i.e. combining immune checkpoint inhibitors with cytotoxics, anti-angiogenesis or targeted therapies) that can no longer be addressed when following standard trial-and-error approaches, but rather by using mathematical-derived algorithms as decision-making tools by investigators for rational design. In routine clinical setting, developing therapeutic drug monitoring of immune checkpoint inhibitors with adaptive dosing strategies has been a long-neglected strategy. Still, substantial improvements might be achieved using dedicated tools for precision medicine and personalized medicine in immunotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Published
2019
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33. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted.

Author

Nguyen TH, Guedj J, Anglaret X, Laouénan C, Madelain V, Taburet AM, Baize S, Sissoko D, Pastorino B, Rodallec A, Piorkowski G, Carazo S, Conde MN, Gala JL, Bore JA, Carbonnelle C, Jacquot F, Raoul H, Malvy D, de Lamballerie X, and Mentré F

Subjects
Adolescent, Adult, Aged, Amides administration & dosage, Antiviral Agents administration & dosage, Child, Child, Preschool, Ebolavirus drug effects, Ebolavirus physiology, Female, Guinea, Hemorrhagic Fever, Ebola virology, Humans, Male, Middle Aged, Pyrazines administration & dosage, Young Adult, Amides pharmacokinetics, Antiviral Agents pharmacokinetics, Hemorrhagic Fever, Ebola drug therapy, Pyrazines pharmacokinetics
Abstract

Background: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations., Methods and Findings: Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality., Conclusions: Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses., Trial Registration: ClinicalTrials.gov NCT02329054.

Published
2017
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