12 results on '"Desvignes, C."'
Search Results
2. Diagnostic en imagerie et histoire naturelle de la vésicule biliaire multicloisonnée : à propos de 4 cas pédiatriques
- Author
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Gazagne, C., primary, Dabadie, A., additional, Aschero, A., additional, Pico, H., additional, Colavolpe, N., additional, Desvignes, C., additional, and Petit, P., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Profil phénotypique des polynucléaires éosinophiles circulants au cours du DRESS et des exanthèmes maculopapuleux médicamenteux avec ou sans éosinophilie sanguine
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Dezoteux, F., Dendooven, A., Duvert Lehembre, S., Maiezza, S., Karimova, E., Becquart, C., Vermersch, A., Faiz, S., Carpentier, O., Modiano, P., Fievet, C., Desvignes, C., Delaunay, E., Soria, A., Oro, S., Lefèvre, G., and Staumont-Sallé, D.
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- 2023
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4. Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.
- Author
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Le Tilly O, Gatault P, Semlali S, Sberro-Soussan R, Passot C, Bertrand D, Desvignes C, Caillard S, Paintaud G, Halimi JM, and Ternant D
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Aged, Dose-Response Relationship, Drug, Young Adult, Complement Inactivating Agents pharmacokinetics, Complement Inactivating Agents administration & dosage, Computer Simulation, Adolescent, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized administration & dosage, Models, Biological, Drug Monitoring methods, Atypical Hemolytic Uremic Syndrome drug therapy, Nonlinear Dynamics
- Abstract
Aims: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model., Methods: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L)., Results: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (V
max = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax /CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively., Conclusions: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2024
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5. A Fab of trastuzumab to treat HER2 overexpressing breast cancer brain metastases.
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Angeli E, Paris J, Le Tilly O, Desvignes C, Gapihan G, Boquet D, Pamoukdjian F, Hamdan D, Rigal M, Poirier F, Lutomski D, Azibani F, Mebazaa A, Herbet A, Mabondzo A, Falgarone G, Janin A, Paintaud G, and Bousquet G
- Abstract
Despite major therapeutic advances for two decades, including the most recently approved anti-HER2 drugs, brain metastatic localizations remain the major cause of death for women with metastatic HER2 breast cancer. The main reason is the limited drug passage of the blood-brain barrier after intravenous injection and the significant efflux of drugs, including monoclocal antibodies, after administration into the cerebrospinal fluid. We hypothesized that this efflux was linked to the presence of a FcRn receptor in the blood-brain barrier. To overcome this efflux, we engineered two Fab fragments of trastuzumab, an anti-HER2 monoclonal antibody, and did a thorough preclinical development for therapeutic translational purpose. We demonstrated the safety and equal efficacy of the Fabs with trastuzumab in vitro, and in vivo using a patient-derived xenograft model of HER2 overexpressing breast cancer. For the pharmacokinetic studies of intra-cerebrospinal fluid administration, we implemented original rat models with catheter implanted into the cisterna magna. After intraventricular administration in rats, we demonstrated that the brain-to-blood efflux of Fab was up to 10 times lower than for trastuzumab, associated with a two-fold higher brain penetration compared to trastuzumab. This Fab, capable of significantly reducing brain-to-blood efflux and enhancing brain penetration after intra-cerebrospinal fluid injection, could thus be a new and original effective drug in the treatment of HER2 breast cancer brain metastases, which will be demonstrated by a phase I clinical trial dedicated to women in resort situations., (© 2024. The Author(s).)
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- 2024
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6. Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.
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Lobet S, Caulet M, Paintaud G, Azzopardi N, Desvignes C, Chautard R, Borg C, Capitain O, Ferru A, Bouché O, Lecomte T, and Ternant D
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- Humans, Bevacizumab, Vascular Endothelial Growth Factor A, Disease-Free Survival, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Fluorouracil, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Rectal Neoplasms
- Abstract
Aims: The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases., Methods: Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival., Results: Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R
0 = 8.4 nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1 ). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival., Conclusion: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship., (© 2023 British Pharmacological Society.)- Published
- 2024
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7. Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial.
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Dupuis-Girod S, Rivière S, Lavigne C, Fargeton AE, Gilbert-Dussardier B, Grobost V, Leguy-Seguin V, Maillard H, Mohamed S, Decullier E, Roux A, Bernard L, Saurin JC, Saroul N, Faure F, Cartier C, Altwegg R, Laccourreye L, Oberti F, Beaudoin M, Dhelens C, Desvignes C, Azzopardi N, Paintaud G, Hermann R, and Chinet T
- Subjects
- Adult, Humans, Middle Aged, Antibodies, Monoclonal, Humanized adverse effects, Bevacizumab adverse effects, Treatment Outcome, Double-Blind Method, Hemorrhage drug therapy, Telangiectasia, Hereditary Hemorrhagic complications, Telangiectasia, Hereditary Hemorrhagic drug therapy
- Abstract
Background: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted., Methods: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment., Results: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm., Conclusion: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)
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- 2023
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8. Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients.
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Lobet S, Paintaud G, Azzopardi N, Passot C, Caulet M, Chautard R, Desvignes C, Capitain O, Tougeron D, Lecomte T, and Ternant D
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- Humans, Cetuximab therapeutic use, Cetuximab pharmacokinetics, Progression-Free Survival, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology
- Abstract
Background and Objective: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS)., Methods: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an E
max model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated., Results: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day-1 ). Estimated time-varying clearance parameters were time-invariant component of CL (CL0 = 0.38 L/day-1 ), time-variant component of CL (CL1 = 0.058 L/day-1 ) and first-order rate of CL1 decreasing over time (kdes = 0.049 day-1 ). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP., Conclusion: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2023
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9. Protein mapping of peanut extract with capillary electrophoresis.
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Villemet L, Cuchet A, Desvignes C, and Sänger-van de Griend CE
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- Electrophoresis, Capillary methods, Plant Extracts metabolism, Proteins metabolism, Allergens, Arachis metabolism
- Abstract
Protein separation can be achieved with different modes of capillary electrophoresis, such as with capillary gel electroporesis (CGE) or with capillary zone electrophoresis (CZE). CZE protein mapping of peanut extract was approached in four different ways, combining neutral-coated or multilayer-coated capillaries with pHs well over or under the isoelectric point range of the proteins of interest. At acidic pHs, the mobility ranges of the major peanut allergens Ara h1, Ara h2, Ara h3, and Ara h6 were identified. Although the pH is a major factor in CZE separation, buffers with different compositions but with the same pH and ionic strength showed significantly different resolutions. Different components of the electrolyte were studied in a multifactorial design of experiment. CE-SDS and CZE proved to be suitable for protein mapping and we were able to distinguish different batches of peanut extract and burned peanut extract., (© 2021 The Authors. Electrophoresis published by Wiley-VCH GmbH.)
- Published
- 2022
- Full Text
- View/download PDF
10. Relevance of Routine Abdominopelvic Ultrasound in Suspected Child Abuse in Children Under 2 years of Age: Review of 15 years of Experience.
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Martin-Champetier A, Caujolle A, Bosdure E, Bresson V, Aschero A, Desvignes C, Colavolpe N, Pico H, Seiler C, Panuel M, Chaumoitre K, Petit P, and Dabadie A
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- Humans, Infant, Retrospective Studies, Tomography, X-Ray Computed methods, Child Abuse diagnosis
- Abstract
In France, the current recommendation is to perform a routine abdominopelvic ultrasound in any child under 2 years of age who is suspected to have been abused. We retrospectively studied the relevance of this practice in our center over the past fifteen years. This was a descriptive, retrospective study of all children under 2 years of age who had been subject to suspected abuse. Abdominal images and reports were reviewed and cross-referenced with possible clinical and biological signs. Four hundred and five children were included between 2006 and 2020, of whom 296 underwent abdominal imaging (2 initial abdominopelvic CT scans, 4 ultrasounds followed by CT scans, and 290 ultrasounds alone). Four examinations revealed traumatic abnormalities related to abuse. These four children all had clinical or biological anomalies. In the absence of clinical or biological signs, no imagery showed any abnormality related to abuse.
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- 2022
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11. The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition.
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Bensalem A, Cartron G, Specks U, Mulleman D, Gyan E, Cornec D, Desvignes C, Casasnovas O, Lamy T, Leprêtre S, Paintaud G, and Ternant D
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- Antigens, CD20 metabolism, Humans, Rituximab pharmacokinetics, Arthritis, Rheumatoid drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Lymphoma, Follicular drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Background and Objectives: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab., Methods: Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates., Results: Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L
0 ) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L0 increased with baseline total metabolic tumor volume (p = 6.10-7 ). In CLL, the second-order target-mediated elimination rate constant (kdeg ) increased with baseline CD20 count on circulating B cells (CD20cir , p = 0.0081)., Conclusions: Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2022
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12. Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment-A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model.
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Ternant D, Le Tilly O, Picon L, Moussata D, Passot C, Bejan-Angoulvant T, Desvignes C, Mulleman D, Goupille P, and Paintaud G
- Abstract
Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R
C 0 = 3.3 nM and RP 0 = 0.46 nM), steady-stated dissociation rates (KC SS = 15.4 nM and KP SS = 0.49 nM), and first-order elimination rates of complexes (kC int = 0.17 day-1 and kP int = 0.0079 day-1 ). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.- Published
- 2021
- Full Text
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