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1. Concentration‐QTc modeling of sitravatinib in patients with advanced solid malignancies

Author

Adam Dickinson, Yong Liu, Artem Uvarov, Thomas Peyret, J. F. Marier, Curtis Chin, and Jonathan Q. Tran

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration‐corrected QT interval (QTc; C‐QTc) modeling was undertaken, using 767 matched concentration‐ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10–200 mg, via a linear mixed‐effects (LME) model. The effect on heart rate (HR)‐corrected QT interval via Fridericia's correction method (QTcF) at the steady‐state maximum concentration (Cmax,ss) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C‐QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95–5.89) ms and 2.94 (0.23–6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst‐case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C‐QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.

Published
2024
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2. Rapid and Accurate Diagnosis of Dermatophyte Infections Using the DendrisCHIP® Technology

Author

Aurore Anton, Mathilde Plinet, Thomas Peyret, Thomas Cazaudarré, Stéphanie Pesant, Yannick Rouquet, Marie-Andrée Tricoteaux, Matthieu Bernier, Jérémy Bayette, Remi Fournier, Mélanie Marguerettaz, Pierre Rolland, Thibaud Bayol, Nadia Abbaoui, Antoine Berry, Xavier Iriart, Sophie Cassaing, Pamela Chauvin, Elodie Bernard, Richard Fabre, and Jean-Marie François

Subjects
dermatophytes, in vitro diagnostic, syndromic approach, multiplex PCR, biochips, microbial cultures, Medicine (General), R5-920
Abstract

Dermatophytosis is a superficial fungal infection with an ever-increasing number of patients. Culture-based mycology remains the most commonly used diagnosis, but it takes around four weeks to identify the causative agent. Therefore, routine clinical laboratories need rapid, high throughput, and accurate species-specific analytical methods for diagnosis and therapeutic management. Based on these requirements, we investigated the feasibility of DendrisCHIP® technology as an innovative molecular diagnostic method for the identification of a subset of 13 pathogens potentially responsible for dermatophytosis infections in clinical samples. This technology is based on DNA microarray, which potentially enables the detection and discrimination of several germs in a single sample. A major originality of DendrisCHIP® technology is the use of a decision algorithm for probability presence or absence of pathogens based on machine learning methods. In this study, the diagnosis of dermatophyte infection was carried out on more than 284 isolates by conventional microbial culture and DendrisCHIP®DP, which correspond to the DendrisCHIP® carrying oligoprobes of the targeted pathogens implicated in dermatophytosis. While convergence ranging from 75 to 86% depending on the sampling procedure was obtained with both methods, the DendrisCHIP®DP proved to identify more isolates with pathogens that escaped the culture method. These results were confirmed at 86% by a third method, which was either a specific RT-PCR or genome sequencing. In addition, diagnostic results with DendrisCHIP®DP can be obtained within a day. This faster and more accurate identification of fungal pathogens with DendrisCHIP®DP enables the clinician to quickly and successfully implement appropriate antifungal treatment to prevent the spread and elimination of dermatophyte infection. Taken together, these results demonstrate that this technology is a very promising method for routine diagnosis of dermatophytosis.

Published
2023
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4. Population pharmacokinetics and exposure‐response analyses of teduglutide in adult and pediatric patients with short bowel syndrome

Author

Jean‐Francois Marier, Claudia Jomphe, Thomas Peyret, and Yi Wang

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract Teduglutide is a recombinant analog of human glucagon‐like peptide‐2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure‐response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged

Published
2021
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6. The DendrisCHIP® Technology as a New, Rapid and Reliable Molecular Method for the Diagnosis of Osteoarticular Infections

Author

Elodie Bernard, Thomas Peyret, Mathilde Plinet, Yohan Contie, Thomas Cazaudarré, Yannick Rouquet, Matthieu Bernier, Stéphanie Pesant, Richard Fabre, Aurore Anton, Cathy Maugis-Rabusseau, and Jean Marie François

Subjects
bone and joint infection, in vitro multiplex diagnostic, biochips, next-generation sequencing, microbial cultures, Medicine (General), R5-920
Abstract

Osteoarticular infections are major disabling diseases that can occur after orthopedic implant surgery in patients. The management of these infections is very complex and painful, requiring surgical intervention in combination with long-term antibiotic treatment. Therefore, early and accurate diagnosis of the causal pathogens is essential before formulating chemotherapeutic regimens. Although culture-based microbiology remains the most common diagnosis of osteoarticular infections, its regular failure to identify the causative pathogen as well as its long-term modus operandi motivates the development of rapid, accurate, and sufficiently comprehensive bacterial species-specific diagnostics that must be easy to use by routine clinical laboratories. Based on these criteria, we reported on the feasibility of our DendrisCHIP® technology using DendrisCHIP®OA as an innovative molecular diagnostic method to diagnose pathogen bacteria implicated in osteoarticular infections. This technology is based on the principle of microarrays in which the hybridization signals between oligoprobes and complementary labeled DNA fragments from isolates queries a database of hybridization signatures corresponding to a list of pre-established bacteria implicated in osteoarticular infections by a decision algorithm based on machine learning methods. In this way, this technology combines the advantages of a PCR-based method and next-generation sequencing (NGS) while reducing the limitations and constraints of the two latter technologies. On the one hand, DendrisCHIP®OA is more comprehensive than multiplex PCR tests as it is able to detect many more germs on a single sample. On the other hand, this method is not affected by the large number of nonclinically relevant bacteria or false positives that characterize NGS, as our DendrisCHIP®OA has been designed to date to target only a subset of 20 bacteria potentially responsible for osteoarticular infections. DendrisCHIP®OA has been compared with microbial culture on more than 300 isolates and a 40% discrepancy between the two methods was found, which could be due in part but not solely to the absence or poor identification of germs detected by microbial culture. We also demonstrated the reliability of our technology in correctly identifying bacteria in isolates by showing a convergence (i.e., same bacteria identified) with NGS superior to 55% while this convergence was only 32% between NGS and microbial culture data. Finally, we showed that our technology can provide a diagnostic result in less than one day (technically, 5 h), which is comparatively faster and less labor intensive than microbial cultures and NGS.

Published
2022
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8. An Efficient and Flexible Stochastic CGRA Mapping Approach

Author

Satyajit Das, Kevin Martin, Thomas Peyret, Philippe Coussy, Indian Institut of Technology [Palakkad] (ITT Palakkad), Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT), Equipe Hardware ARchitectures and CAD tools (Lab-STICC_ARCAD), Institut Mines-Télécom [Paris] (IMT)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique (IMT Atlantique), Université de Bretagne Sud (UBS), Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
instrumentation, Electronic architecture, Hardware and Architecture, Coarse-Grained Reconfigurable Array (CGRA), stochastic mapping, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], mapping, Software
Abstract

Coarse-Grained Reconfigurable Array (CGRA) architectures are promising high-performance and power-efficient platforms. However, mapping applications efficiently on CGRA is a challenging task. This is known to be an NP complete problem. Hence, finding good mapping solutions for a given CGRA architecture within a reasonable time is complex. Additionally, finding scalability in compilation time and memory footprint for large heterogeneous CGRAs is also a well known problem. In this article, we present a stochastic mapping approach that can efficiently explore the architecture space and allows finding best of solutions while having limited and steady use of memory footprint. Experimental results show that our compilation flow allows to reach performances with low-complexity CGRA architectures that are as good as those obtained with more complex ones thanks to the better exploration of the mapping solution space. Parameters considered in our experiments are number of tiles, Register File (RF) size, number of load/store (LS) units, network topologies, and so on. Our results demonstrate that high-quality compilation for a wide range of applications is possible within reasonable run-times. Experiments with several DSP benchmarks show that the best CGRA configuration from the architectural exploration surpasses an ultra low-power DSP optimized RISC-V CPU to achieve up to 15.28× (with an average of 6× and minimum of 3.4×) performance gain and 29.7× (with an average of 13.5× and minimum of 6.3×) energy gain with an area overhead of 1.5× only.

Published
2022

10. Population pharmacokinetics and exposure‐response analyses of teduglutide in adult and pediatric patients with short bowel syndrome

Author

Thomas Peyret, J.F. Marier, Claudia Jomphe, and Yi Wang

Subjects
Adult, Short Bowel Syndrome, medicine.medical_specialty, Parenteral Nutrition, Adolescent, Population, Cmax, Renal function, RM1-950, Teduglutide, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, Article, chemistry.chemical_compound, Young Adult, Pharmacokinetics, Gastrointestinal Agents, Japan, Internal medicine, Medicine, Humans, Dosing, General Pharmacology, Toxicology and Pharmaceutics, education, Child, Aged, Volume of distribution, education.field_of_study, business.industry, General Neuroscience, Research, Infant, General Medicine, Articles, Middle Aged, Short bowel syndrome, medicine.disease, chemistry, Child, Preschool, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business, Peptides
Abstract

Teduglutide is a recombinant analog of human glucagon‐like peptide‐2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure‐response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged

Published
2021

12. The DendrisCHIP

Author

Elodie, Bernard, Thomas, Peyret, Mathilde, Plinet, Yohan, Contie, Thomas, Cazaudarré, Yannick, Rouquet, Matthieu, Bernier, Stéphanie, Pesant, Richard, Fabre, Aurore, Anton, Cathy, Maugis-Rabusseau, and Jean Marie, François

Abstract

Osteoarticular infections are major disabling diseases that can occur after orthopedic implant surgery in patients. The management of these infections is very complex and painful, requiring surgical intervention in combination with long-term antibiotic treatment. Therefore, early and accurate diagnosis of the causal pathogens is essential before formulating chemotherapeutic regimens. Although culture-based microbiology remains the most common diagnosis of osteoarticular infections, its regular failure to identify the causative pathogen as well as its long-term modus operandi motivates the development of rapid, accurate, and sufficiently comprehensive bacterial species-specific diagnostics that must be easy to use by routine clinical laboratories. Based on these criteria, we reported on the feasibility of our DendrisCHIP

Published
2022

14. Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

Author

Thomas Peyret and Kannan Krishnan

Subjects
Toxicology. Poisons, RA1190-1270
Abstract

The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained from in vivo animal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo Vmax (μmol/h/kg bw rat) to the Km (μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R2=0.8; leave-one-out cross-validation Q2=0.75) for CLint normalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat) from the input data on log Pow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint) to minimum (using UMCI for CLint) AUC predicted by the QPPR-PBPK model was 1.36±0.4 and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs.

Published
2012
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15. Introduction d'aléas dans le processus de projection d'applications sur CGRA

Author

Satyajit Das, Kevin Martin, Thomas Peyret, Philippe Coussy, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC (UMR 6285), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA))

Subjects
instrumentation, [INFO.INFO-AR]Computer Science [cs]/Hardware Architecture [cs.AR], reconfigurable architecture, assignation, projection, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], computer architecture, aléatoire, CGRA, electronic architecture, [SPI.TRON]Engineering Sciences [physics]/Electronics, ordonnancement
Abstract

National audience; Les architectures reconfigurables à gros grains offrent un compromis flexibilité-performance intéressant à travers les nombreuses unités de calculs élémentaires qu'elles proposent. Cependant, projeter automatiquement une application sur une architecture reconfigurable à gros grain est un processus complexe qui nécessite d'explorer un vaste espace de solutions. Cet article propose d'étudier l'apport d'aléas dans le processus de projection. L'introduction d'aléas est effectué en particulier dans les étapes d'ordonnancement et d'assignation. Différentes stratégies permettant de garantir un nombre minimum et maximum de solutions sont présentées. Les résultats montrent que notre méthode, couplée à une approche de transformation du graphe d'application, explore mieux l'espace de solutions et permet de trouver la latence la plus courte.

Published
2016

16. Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation

Author

Kelong Han, Jin Jin, Michela Casanova, Sridharan Gururangan, Nathalie H. Gosselin, Jacques Grill, Johannes H. M. Merks, Fariba Navid, Angelica Quartino, David E. Allison, Najat C. Daw, Maura Massimino, Thomas Peyret, CCA -Cancer Center Amsterdam, and Paediatric Oncology

Subjects
Oncology, medicine.medical_specialty, paediatric, Adolescent, genetic structures, Bevacizumab, Population, Angiogenesis Inhibitors, Pharmacology, Models, Biological, Corrections, 030226 pharmacology & pharmacy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, external validation, Pharmacokinetics, Paediatric cancer, Neoplasms, Internal medicine, medicine, Humans, Pharmacology (medical), Dosing, Child, education, Paediatric patients, central nervous system tumour, education.field_of_study, business.industry, body surface area, Body Weight, dosing strategy, External validation, Infant, eye diseases, Pharmacokinetic analysis, Child, Preschool, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, sense organs, Paediatric Clinical Pharmacology, business, medicine.drug
Abstract

Aim The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. Methods Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5 – 21 years), body weight (BWT; 5.9 – 125 kg), and regimens (5 – 15 mg kg–1 biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady‐state exposure was simulated under BWT‐based, body surface area (BSA)‐based, ideal body weight (IBW)‐based, and tier‐based doses. NONMEM and R were used for analyses. Results Typical estimates of clearance, central volume of distribution (V1), and median half‐life were 9.04 ml h–1, 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (Cmin) and 29% higher peak (Cmax) concentrations. BWT‐adjusted clearance and V1 remained unchanged across ages. Paediatric Cmin was similar to adult Cmin under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier‐based doses. Conclusions BWT‐adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA‐based, IBW‐based, and tier‐based doses offered no substantial advantage over the BWT‐based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

Published
2016

17. An integrated QSPR–PBPK modelling approach for in vitro–in vivo extrapolation of pharmacokinetics in rats

Author

Thomas Peyret, Kannan Krishnan, and E Kamgang

Subjects
Volatile Organic Compounds, Physiologically based pharmacokinetic modelling, Quantitative structure–activity relationship, Chromatography, Metabolic Clearance Rate, Stereochemistry, Chemistry, Kinetics, INT, Bioengineering, General Medicine, Models, Theoretical, Toxicology, Rats, Partition coefficient, Liver, Pharmacokinetics, In vivo, Bioaccumulation, Drug Discovery, Animals, Molecular Medicine, Tissue Distribution
Abstract

In vitro data on metabolism and partitioning may be integrated within physiologically-based pharmacokinetic (PBPK) models to provide simulations of the kinetics and bioaccumulation of chemicals in intact organisms. Quantitative structure-property relationship (QSPR) modelling of available in vitro data may be performed to predict metabolism rates and partition coefficients (PCs) for developing in vivo PBPK models. The objective of the present study was to develop an integrated QSPR-PBPK modelling approach for the conduct of in vitro to in vivo extrapolation. For this purpose, data on rat blood:air (P(b)) and fat:air (P(f)) PCs, as well as intrinsic metabolic clearance (CL(int)) obtained using rat liver slices for some C(5)-C(10) volatile organic compounds (VOCs) were compiled from the literature. Multilinear additive QSPR models for P(f), P(b) and CL(int) were developed based on the number and nature of molecular fragments in these VOCs (CH(3), CH(2), CH, C, C=C, H, benzene ring and H in benzene ring structure). The mean estimated/experimental (est/exp) ratios (+/-SD; range) were 1.0 (+/-0.04; 0.93 - 1.06) for log P(f), 1.08 (+/-0.26; 0.70 - 1.62) for log P(b), and 1.07 (+/- 0.21; 0.80 - 1.44) for CL(int). By accounting for the difference in the content of neutral lipids in fat and other tissues, the liver : air and muscle : air PCs of the compounds investigated in this study, with the excerption of n-decane, were adequately predicted from P(f). Integrating the QSPRs for P(f), P(b) and CL(int) within a rat PBPK model, simulations of inhalation pharmacokinetics of several VOCs were generated on the basis of molecular structure, for a given exposure scenario. The integrated QSPR-PBPK model developed in this study is a potentially useful tool for predicting in vivo kinetics and bioaccumulation of chemicals in rats under poor data situations.

Published
2008

18. Population pharmacokinetic and pharmacodynamic analyses from a 4-month intradose escalation and its subsequent 12-month dose titration studies for a human monoclonal anti-FGF23 antibody (KRN23) in adults with X-linked hypophosphatemia

Author

Thomas Peyret, Erik A. Imel, Nathalie H. Gosselin, Thomas O. Carpenter, J.F. Marier, and Xiaoping Zhang

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, Antibodies, Monoclonal, Humanized, Metabolic bone disease, Phosphates, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), Dosing, Vitamin D, education, Pharmacology, education.field_of_study, Chemistry, Half-life, Antibodies, Monoclonal, Middle Aged, X-linked hypophosphatemia, medicine.disease, Fibroblast Growth Factors, Fibroblast Growth Factor-23, 030104 developmental biology, Endocrinology, Pharmacodynamics, Female, Familial Hypophosphatemic Rickets, Hypophosphatemia, Half-Life
Abstract

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses ≥0.1 mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing and progressively increased following each of the initial 4 doses with comparable peak values attained following the sixth through tenth doses with a slight decrease thereafter. A PK-PD model with a maximum effect (Emax ) and a time-varying effective concentration to reach 50% of Emax (EC50,t ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.

Published
2015

19. Procédé et dispositif de tolérance aux fautes sur des composants électroniques

Author

Thomas Peyret, Thevenin Mathieu, Gwenole Corre, Philippe Coussy, Kevin Martin, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), and Martin, Kevin

Subjects
[SPI.TRON] Engineering Sciences [physics]/Electronics, [SPI.TRON]Engineering Sciences [physics]/Electronics
Published
2015

20. Architecture matérielle et flot de programmation associé pour la conception de systèmes numériques tolérants aux fautes

Author

Thomas Peyret, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université de Bretagne Sud, Philippe Coussy, Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA))

Subjects
Control and Data Flow Graph, Tolérance aux fautes, Coarse Grained Reconfigurable Architecture, Triplication, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Ordonnancement, Fault tolerance, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Architecture Reconfigurable à Gros Grains, Assignation, [SPI.TRON]Engineering Sciences [physics]/Electronics
Abstract

Whether in automotive with heat stress or in aerospace and nuclear field subjected to cosmic,neutron and gamma radiation, the environment can lead to the development of faults in electronic systems. These faults, which can be transient or permanent, will lead to erroneous results that are unacceptable in some application contexts. The use of so-called rad-hard components is sometimes compromised due to their high costs and supply problems associated with export rules.This thesis proposes a joint hardware and software approach independent of integration technology for using digital programmable devices in environments that generate faults. Our approach includes the definition of a Coarse Grained Reconfigurable Architecture (CGRA) able to execute entire application code but also all the hardware and software mechanisms to make it tolerant to transient and permanent faults. This is achieved by the combination of redundancy and dynamic reconfiguration of the CGRA based on a library of configurations generated by a complete conception flow. This implemented flow relies on a flow to map a code represented as a Control and Data Flow Graph (CDFG) on the CGRA architecture by obtaining directly a large number of different configurations and allows to exploit the full potential of architecture.This work, which has been validated through experiments with applications in the field of signal and image processing, has been the subject of two publications in international conferences and of two patents.; Que ce soit dans l’automobile avec des contraintes thermiques ou dans l’aérospatial et le nucléaire soumis à des rayonnements ionisants, l’environnement entraîne l’apparition de fautes dans les systèmes électroniques. Ces fautes peuvent être transitoires ou permanentes et vont induire des résultats erronés inacceptables dans certains contextes applicatifs. L’utilisation de composants dits « rad-hard » est parfois compromise par leurs coûts élevés ou les difficultés d’approvisionnement liés aux règles d’exportation.Cette thèse propose une approche conjointe matérielle et logicielle indépendante de la technologie d’intégration permettant d’utiliser des composants numériques programmables dans des environnements susceptibles de générer des fautes. Notre proposition comporte la définition d’une Architecture Reconfigurable à Gros Grains (CGRA) capable d’exécuter des codes applicatifs complets mais aussi l’ensemble des mécanismes matériels et logiciels permettant de rendre cette architecture tolérante aux fautes. Ce résultat est obtenu par l’association de redondance et de reconfiguration dynamique du CGRA en s’appuyant sur une banque de configurations généréepar une chaîne de programmation complète. Cette chaîne outillée repose sur un flot permettant de porter un code sous forme de Control and Data Flow Graph (CDFG) sur l’architecture en obtenant un grand nombre de configurations différentes et qui permet d’exploiter au mieux le potentiel de l’architecture.Les travaux, qui ont été validés aux travers d’expériences sur des applications du domaine du traitement du signal et de l’image, ont fait l’objet de publications en conférences internationales et de dépôts de brevets.

Published
2014

21. Sa1576 Exposure-Response Relationship of Obeticholic Acid for Alkaline Phosphatase and Total Bilirubin in Patients With Primary Biliary Cirrhosis (PBC)

Author

Nathalie H. Gosselin, Leng Hong Pheng, Jeffrey E. Edwards, Carl LaCerte, Thomas Peyret, David Shapiro, and J.F. Marier

Subjects
medicine.medical_specialty, Hepatology, Bilirubin, business.industry, Gastroenterology, Obeticholic acid, medicine.disease, chemistry.chemical_compound, Primary biliary cirrhosis, chemistry, Internal medicine, medicine, Alkaline phosphatase, In patient, business, Exposure response
Published
2016

22. Efficient application mapping on CGRAs based on backward simultaneous scheduling/binding and dynamic graph transformations

Author

Philippe Coussy, Gwenolé Corre, Kevin Martin, Thomas Peyret, Mathieu Thevenin, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Computer science, dynamic graph transformations, coarse grained reconfigurable architecture, Image processing, 010103 numerical & computational mathematics, 02 engineering and technology, Dynamic priority scheduling, Parallel computing, 01 natural sciences, Scheduling (computing), data flow graph, Reconfigurable architectures, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, 0202 electrical engineering, electronic engineering, information engineering, backward traversal, 0101 mathematics, Coarse-Grained Reconfigurable Architecture (CGRA), formal model, Routing, Data-flow analysis, instrumentation, Space exploration, Electronic architecture, automated synthesis flow, Scheduling, [INFO.INFO-AO]Computer Science [cs]/Computer Arithmetic, Registers, Dynamic scheduling, Binding, [INFO.INFO-IA]Computer Science [cs]/Computer Aided Engineering, CGRA, backward simultaneous scheduling-binding, digital signal domain, [SPI.TRON]Engineering Sciences [physics]/Electronics, 020202 computer hardware & architecture, Tree traversal, Mapping, application mapping, compilation, Graph (abstract data type), image processing domain
Abstract

International audience; Mapping an application on a coarse grained reconfigurable architecture (CGRA) is a complex task which is still often completely or partially realized manually. This paper presents an automated synthesis flow based on simultaneous scheduling and binding steps. The proposed method uses a backward traversal of the formal model obtained after compilation and dynamically transforms it when needed. Our approach is compared with state of the art techniques and its interest is shown through the mapping of several applications from digital signal and image processing domain.

Published
2014

23. An automated design approach to map applications on CGRAs

Author

Gwenolé Corre, Thomas Peyret, Philippe Coussy, Kevin Martin, Mathieu Thevenin, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Data Flow Graph (DFG), Electronic architecture, Computer science, Scheduling, Real-time computing, Design flow, Binding, [INFO.INFO-IA]Computer Science [cs]/Computer Aided Engineering, Scheduling (computing), Design Aids, Computer architecture, Mapping, B.5.2 [Register-Transfer-Level Implementation]: Design Aids - Automatic synthesis, Control Data Flow Graph (CDFG), [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Instrumentation, Coarse-Grained Reconfigurable Architectures (CGRA)
Abstract

International audience; Coarse-Grained Reconfigurable Architectures (CGRAs) are promising high-performance and power-efficient platforms. However, their uses are still limited by the capability of mapping tools. This abstract paper outlines a new automated design flow to map applications on CGRAs. The interest of our method is shown through comparison with state of the art approaches.

Published
2014

24. Ordonnancement, assignation et transformations dynamiques de graphe simultanés pour projeter efficacement des applications sur CGRAs

Author

Thomas Peyret, Gwenolé Corre, Mathieu Thevenin, Kevin Martin, Philippe Coussy, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Pascal Felber, Laurent Philippe, Etienne Riviere, Arnaud Tisserand, Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Peyret, Thomas, and Pascal Felber, Laurent Philippe, Etienne Riviere, Arnaud Tisserand

Subjects
[INFO.INFO-AR]Computer Science [cs]/Hardware Architecture [cs.AR], [INFO.INFO-AR] Computer Science [cs]/Hardware Architecture [cs.AR], Coarse Grained Reconfigurable Architecture, Electronic architecture, B.5.2 [Register-Transfer-Level Implementation]: Design Aids - Automatic synthesis, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Ordonnancement, latency time, graph, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, signal processing, CGRA, Assignation
Abstract

National audience; Porter une application sur une architecture reconfigurable à gros grain est une tâche complexe qui reste encore souvent réalisée entièrement ou partiellement manuellement. Cet article présente un flot original de synthèse automatisé basé sur des étapes d'ordonnancement et d'assignation simultanées. L'approche proposée parcourt en sens inverse les noeuds du modèle formel extrait à partir du code de l'application compilé pour le transformer dynamiquement uniquement si nécessaire. Les résultats des expériences montrent que l'approche proposée permet une meilleure exploration de l'espace de solution et obtient la meilleure latence dans 90% des cas.

Published
2014

25. A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals

Author

Patrick Poulin, Thomas Peyret, and Kannan Krishnan

Subjects
Pharmacology, Micro level, Physiologically based pharmacokinetic modelling, Prescription Drugs, Chemical compound, Muscles, Toxicology, Models, Biological, Biological materials, Biological fluid, Rats, Partition coefficient, chemistry.chemical_compound, Liver metabolism, chemistry, Adipose Tissue, Liver, Partition (number theory), Animals, Environmental Pollutants, Algorithm, Algorithms, Phospholipids, Forecasting
Abstract

The algorithms in the literature focusing to predict tissue:blood PC (P(tb)) for environmental chemicals and tissue:plasma PC based on total (K(p)) or unbound concentration (K(pu)) for drugs differ in their consideration of binding to hemoglobin, plasma proteins and charged phospholipids. The objective of the present study was to develop a unified algorithm such that P(tb), K(p) and K(pu) for both drugs and environmental chemicals could be predicted. The development of the unified algorithm was accomplished by integrating all mechanistic algorithms previously published to compute the PCs. Furthermore, the algorithm was structured in such a way as to facilitate predictions of the distribution of organic compounds at the macro (i.e. whole tissue) and micro (i.e. cells and fluids) levels. The resulting unified algorithm was applied to compute the rat P(tb), K(p) or K(pu) of muscle (n=174), liver (n=139) and adipose tissue (n=141) for acidic, neutral, zwitterionic and basic drugs as well as ketones, acetate esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons and ethers. The unified algorithm reproduced adequately the values predicted previously by the published algorithms for a total of 142 drugs and chemicals. The sensitivity analysis demonstrated the relative importance of the various compound properties reflective of specific mechanistic determinants relevant to prediction of PC values of drugs and environmental chemicals. Overall, the present unified algorithm uniquely facilitates the computation of macro and micro level PCs for developing organ and cellular-level PBPK models for both chemicals and drugs.

Published
2010

26. Physiologically Based Toxicokinetic (PBTK) Modeling in Ecotoxicology

Author

Thomas Peyret and Kannan Krishnan

Subjects
Quantitative structure–activity relationship, Physiologically based pharmacokinetic modelling, Environmental chemistry, Ecotoxicological risk, Ecotoxicology, %22">Fish , Model development, Biochemical engineering, Biology
Abstract

Physiologically based toxicokinetic [(PBTK), or alternatively referred to as physiologically based pharmacokinetic (PBPK)] models are quantitative descriptions of absorption, distribution, metabolism, and excretion of chemicals in biota. PBTK models are increasingly being used as an effective tool for designing toxicology experiments and for conducting extrapolations essential for risk assessments. This chapter describes the basic concepts, equations, parameters, and software essential for developing PBTK models. QSAR methods for estimating input parameters as well as data sources containing relevant parameters for model development in rats, mice, cattle, birds, and fish are summarized. Model templates for creating PBTK models in fish and terrestrial species are presented. Several examples of model simulations are presented along with a brief discussion of how PBTK models can be applied to make significant advances in ecotoxicology and ecotoxicological risk assessments.

Published
2009

27. Population pharmacokinetics of bevacizumab in cancer patients with external validation

Author

Kelong Han, Thomas Peyret, Nathalie H. Gosselin, David E. Allison, Sandhya Girish, Jin Jin, Angelica Quartino, and Mathilde Marchand

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, genetic structures, Angiogenesis Inhibitors, Clinical Trials, Phase IV as Topic, Toxicology, 0302 clinical medicine, Japan, Neoplasms, Tissue Distribution, Pharmacology (medical), Population pharmacokinetics, Cancer, Clinical Trials, Phase I as Topic, External validation, Bevacizumab, 030220 oncology & carcinogenesis, Original Article, Female, Half-Life, medicine.drug, Adult, medicine.medical_specialty, Pharmacology toxicology, Models, Biological, Drug Administration Schedule, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Sex Factors, Asian People, Pharmacokinetics, Internal medicine, medicine, Humans, Intensive care medicine, Pharmacology, Asian, Dose-Response Relationship, Drug, business.industry, medicine.disease, eye diseases, 030104 developmental biology, Clinical Trials, Phase III as Topic, sense organs, business
Abstract

Background Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics. Methods Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules. Results Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were −2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance. Conclusions A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3079-6) contains supplementary material, which is available to authorized users.

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28. Procédé et dispositif d'architecture configurable à gros grains pour exécuter l'intégralité d'un code

Author

Thomas Peyret, Thevenin Mathieu, Gwenole Corre, Kevin Martin, Philippe Coussy, Laboratoire Capteurs et Architectures Electroniques (LCAE), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lab-STICC_UBS_CACS_MOCS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Martin, Kevin, Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SPI.TRON] Engineering Sciences [physics]/Electronics, [SPI.TRON]Engineering Sciences [physics]/Electronics

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