/. Inserm and . Servier, Karl a obtenu un poste chez Servier à l

J. De-février-À-juin-de and . Bertrand, Depuis octobre, nous avons obtenu un contrat avec les laboratoires Servier pour 3 ans, 2005.

/. Inserm and . Servier, Julie doit soutenir sa thèse à la fin de l'année Elle doit ensuite effectuer un stage post-doctoral dans l'équipe de David Balding à l'University College of London, Elle se destine ensuite à une carrière dans un organisme de recherches comme l'INSERM. Les travaux de recherche réalisés lors de son stage et sa thèse sont présentés en section 2.2.4, 2009.

W. Couët, L'objectif de ce stage est de déterminer des protocoles adaptés pour l'estimation des paramètres de modèles représentant la dynamique de populations bactériennes ou fongiques après administration d'antibiotiques ou d'antifongiques. Nous nous intéressons notamment à la capacité du protocole à discriminer entre différents modèles représentant l

S. Chevret, F. Mentré, and P. Ravaud, Dans ce master, je suis co-responsable du moduleUtilisation de logiciels statistiques

J. 'enseigne-Également-dans-les-modules, Modèles statistiques en évaluation thérapeutique" et "Modèles stochastiques -Modèles mixtes

F. Mentré, F. Pousset, E. Comets, B. Plaud, B. Diquet et al., Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients*, Clinical Pharmacology & Therapeutics, vol.23, issue.1, pp.64-78, 1998.
DOI : 10.1016/S0009-9236(98)90122-9

G. Aymard, M. Legrand, E. Comets, F. Mentré, and B. Diquet, Rapid and simple micromethod for the quantification of fluindione in human plasma using high-performance liquid chromatography, Journal of Chromatography B: Biomedical Sciences and Applications, vol.707, issue.1-2, pp.169-173, 1998.
DOI : 10.1016/S0378-4347(97)00587-2

E. Comets, F. Mentré, F. Pousset, B. Diquet, G. Montalescot et al., Modeling INR Data to Predict Maintenance Fluindione Dosage, Therapeutic Drug Monitoring, vol.20, issue.6, pp.631-639, 1998.
DOI : 10.1097/00007691-199812000-00009

E. Comets, F. Mentré, F. Nimmerfall, R. Kawai, I. Mueller et al., Nonparametric analysis of the absorption profile of octreotide in rabbits from long-acting release formulation OncoLAR, Journal of Controlled Release, vol.59, issue.2, pp.197-205, 1999.
DOI : 10.1016/S0168-3659(98)00194-1

E. Comets, F. Mentré, R. Kawai, F. Nimmerfall, P. Marbach et al., Modeling the Kinetics of Release of Octreotide from Long???Acting Formulations Injected Intramuscularly in Rabbits, Journal of Pharmaceutical Sciences, vol.89, issue.9, pp.1123-1156, 2000.
DOI : 10.1002/1520-6017(200009)89:9<1123::AID-JPS4>3.0.CO;2-K

E. Comets, F. Pousset, F. Mentré, B. Diquet, G. Montalescot et al., Prediction of Fluindione Maintenance Dosage Hampered by Large Intraindividual Variability, Therapeutic Drug Monitoring, vol.22, issue.6, pp.668-75, 2000.
DOI : 10.1097/00007691-200012000-00005

E. Comets and F. Mentré, EVALUATION OF TESTS BASED ON INDIVIDUAL VERSUS POPULATION MODELING TO COMPARE DISSOLUTION CURVES, Journal of Biopharmaceutical Statistics, vol.11, issue.3, pp.107-130, 2001.
DOI : 10.1081/BIP-100107652

E. Comets, F. Mentré, P. Grass, R. Kawai, P. Marbach et al., Population pharmacodynamic analysis of octreotide in acromegalic patients, Clinical Pharmacology & Therapeutics, vol.73, issue.1, pp.95-106, 2003.
DOI : 10.1067/mcp.2003.6

M. Legrand, E. Comets, G. Aymard, R. Tubiana, C. Katlama et al., An in vivo Pharmacokinetic/Pharmacodynamic Model for Antiretroviral Combination, HIV Clinical Trials, vol.4, issue.3, pp.170-83, 2003.
DOI : 10.1310/77YN-GDMU-95W3-RWT7

E. Comets, K. Ikeda, P. Hoff, P. Fumoleau, J. Wenders et al., Comparison of the Pharmacokinetics of S-1, an Oral Anticancer Agent, in Western and Japanese Patients, Journal of Pharmacokinetics and Pharmacodynamics, vol.30, issue.4, pp.257-83, 2003.
DOI : 10.1023/A:1026142601822
URL : https://hal.archives-ouvertes.fr/inserm-00189555

S. Barraud-de-lagerie, E. Comets, C. Gautrand, C. Fernandez, D. Auchere et al., Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice, British Journal of Pharmacology, vol.45, issue.7, pp.1214-1236, 2004.
DOI : 10.1038/sj.bjp.0705721

C. Jamois, E. Comets, F. Mentré, S. Marion, R. Farinotti et al., Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2, Cancer Chemotherapy and Pharmacology, vol.50, issue.1
DOI : 10.1007/s00280-004-0824-z

S. Marchand, A. Forsell, M. Chenel, E. Comets, I. Lamarche et al., Norfloxacin Blood-Brain Barrier Transport in Rats Is Not Affected by Probenecid Coadministration, Antimicrobial Agents and Chemotherapy, vol.50, issue.1, pp.371-374, 2006.
DOI : 10.1128/AAC.50.1.371-373.2006

K. Brendel, E. Comets, C. Laffont, C. Laveille, and F. Mentré, Metrics for External Model Evaluation with an Application to the Population Pharmacokinetics of Gliclazide, Pharmaceutical Research, vol.91, issue.9, pp.2036-2085, 2006.
DOI : 10.1007/s11095-006-9067-5
URL : https://hal.archives-ouvertes.fr/inserm-00189557

K. Brendel, C. Dartois, E. Comets, A. Lemenuel-diot, C. Laveille et al., Are Population Pharmacokinetic and/or Pharmacodynamic Models Adequately Evaluated?, Clinical Pharmacokinetics, vol.33, issue.3, pp.221-255, 2007.
DOI : 10.2165/00003088-200746030-00003
URL : https://hal.archives-ouvertes.fr/inserm-00159124

E. Comets, C. Verstuyft, M. Lavielle, P. Jaillon, L. Becquemont et al., Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters, European Journal of Clinical Pharmacology, vol.92, issue.5, pp.437-486, 2007.
DOI : 10.1007/s00228-007-0269-5
URL : https://hal.archives-ouvertes.fr/inserm-00146888

S. Retout, E. Comets, A. Samson, and F. Mentré, Design in nonlinear mixed effects models: Optimization using the Fedorov???Wynn algorithm and power of the Wald test for binary covariates, Statistics in Medicine, vol.39, issue.28, pp.5162-79, 2007.
DOI : 10.1002/sim.2910
URL : https://hal.archives-ouvertes.fr/hal-00263513

C. Dartois, K. Brendel, E. Comets, C. Laffont, C. Laveille et al., Overview of model-building strategies in population PK/PD analyses: 2002???2004 literature survey, British Journal of Clinical Pharmacology, vol.4, issue.5, pp.603-615, 2007.
DOI : 10.1007/s10928-006-9046-9
URL : https://hal.archives-ouvertes.fr/inserm-00159122

C. Miceli-richard, E. Comets, C. Verstuyft, R. Tamouza, P. Loiseau et al., A single tumor necrosis factor haplotype influences response to adalimumab in rheumatoid arthritis, Annals of the Rheumatic Diseases, vol.57, pp.478-84, 2007.

C. Miceli-richard, P. Loiseau, E. Comets, X. Puechal, E. Hachulla et al., gene functional polymorphism with Sj??gren's syndrome, Arthritis & Rheumatism, vol.8, issue.12, pp.3989-94, 2007.
DOI : 10.1002/art.23142

E. Comets, K. Brendel, and F. Mentré, Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The npde add-on package for R, Computer Methods and Programs in Biomedicine, vol.90, issue.2, pp.154-66, 2008.
DOI : 10.1016/j.cmpb.2007.12.002
URL : https://hal.archives-ouvertes.fr/inserm-00274332

J. Bertrand, E. Comets, and F. Mentré, Comparison of Model-Based Tests and Selection Strategies to Detect Genetic Polymorphisms Influencing Pharmacokinetic Parameters, Journal of Biopharmaceutical Statistics, vol.5, issue.6, pp.1084-102, 2008.
DOI : 10.1111/j.1525-1438.2006.00593.x
URL : https://hal.archives-ouvertes.fr/inserm-00339183

E. Comets and S. Zohar, A Survey of the Way Pharmacokinetics are Reported in Published Phase I Clinical Trials, with an Emphasis on Oncology, Clinical Pharmacokinetics, vol.14, issue.3, pp.387-95, 2009.
DOI : 10.2165/00003088-200948060-00004
URL : https://hal.archives-ouvertes.fr/inserm-00409057

C. Miceli-richard, N. Gestermann, M. Ittah, E. Comets, P. Loiseau et al., promoter is a strong risk factor for primary Sj??gren's syndrome, Arthritis & Rheumatism, vol.182, issue.7, pp.1991-1998, 2009.
DOI : 10.1002/art.24662

S. Retout, E. Comets, C. Bazzoli, and F. Mentré, Design optimisation in nonlinear mixed effects models using cost functions : application to a joint model of infliximab and methotrexate pharmacokinetics, Communications in Statistics, vol.38, pp.1-18, 2009.

J. Bertrand, E. Comets, C. Laffont, M. Chenel, and F. Mentré, Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm, Journal of Pharmacokinetics and Pharmacodynamics, vol.30, issue.4, pp.317-356, 2009.
DOI : 10.1007/s10928-009-9124-x
URL : https://hal.archives-ouvertes.fr/inserm-00406739

C. Abbara, J. Rousseau, A. Turcan, G. Lallement, E. Comets et al., Pharmacokinetic analysis of diazepam liberation from its prodrug in healthy volunteers : noncompartmental approach and compartmental modelling, British Journal of Clinical Pharmacology, vol.15, pp.1390-1397, 2009.

K. Brendel, E. Comets, C. Laffont, and F. Mentré, Evaluation of different tests based on observations for external model evaluation of population analyses, Journal of Pharmacokinetics and Pharmacodynamics, vol.51, issue.1, pp.49-65, 2010.
DOI : 10.1007/s10928-009-9143-7
URL : https://hal.archives-ouvertes.fr/inserm-00448559

E. Guémas, T. Waegemans, E. Comets, and F. Mentré, Optimal pharmacokinetics study design for a new intravenous immunoglobulin in primary immunodeficiency disorders, European Journal of Clinical Pharmacology, 2009.

E. Comets, F. Mentré, R. Kawai, P. Marbach, and J. Vonderscher, Evaluation of tests based on individual versus population modelling to compare dissolution curves, Population Approach Group in Europe, 2000.

E. Comets, F. Mentré, R. Kawai, P. Marbach, and J. Vonderscher, Prediction intervals of the pharmacokinetic profile of OncoLAR, a long-acting formulation of octreotide in rabbits, XX th International Biometric Conference, 2000.

E. Comets, K. Ikeda, P. Hoff, P. Fumoleau, J. Wenders et al., Population pharmacokinetic analysis of TS-1 : comparison between Japanese and Western patients, 39th annual meeting of the Japan Society of Clinical Oncology, 2001.

E. Comets, K. Ikeda, and Y. Tanigawara, Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients. 12th meeting of the Population Approach Group in Europe, pp.12-13, 2003.
URL : https://hal.archives-ouvertes.fr/inserm-00189555

E. Comets, K. Ikeda, and Y. Tanigawara, Exposure-toxicity relationship of S-1 in Western and Japanese patients, 2nd Pharmaceutical Sciences World Congress, 2004.

E. Comets, Exposure-toxicity relationship of S-1 in Western and Japanese patients, JOBIM, 2006.

E. Comets, F. Mentré, F. Pousset, B. Plaud, B. Diquet et al., Application of an indirect response model to four clotting factors in patients under fluindione therapy, IBC 2nd Annual Conference : Pharmacokinetic?Pharmacodynamic Analysis II : Accelerating Drug Discovery and Development, 1996.

E. Comets, F. Mentré, F. Nimmerfall, R. Kawai, I. Mueller et al., Nonparametric analysis of the release profile of octreotide from long?acting formulation Sandostatin LAR, IBC 3rd Annual Conference : Pharmacokinetic?pharmacodynamic analysis, 1997.

F. Pousset, F. Mentré, E. Comets, G. Montalescot, B. Diquet et al., Savons-nous équilibrer un traitement anticoagulant oral ? Congrès français de cardiologie, Archives des maladies du coeur et des vaisseaux, p.18, 2000.

F. Mentré, B. Diquet, E. Comets, F. Pousset, and A. Mallet, Lechat Ph, the FFAACS investigators. Variability of fluindione pharmacokinetics and pharmacodynamics in patients, World Conference on Clinical Pharmacology and Therapeutics, 2000.

E. Comets, F. Mentré, P. Grass, R. Kawai, P. Marbach et al., Population pharmacodynamic analysis of octreotide in acromegalic patients, Fourth International Symposium on Measurement and kinetics of in vivo drug effects, pp.24-27, 2002.
DOI : 10.1067/mcp.2003.6

C. Gautrand, S. Barraud-de-lagerie, E. Comets, C. Fernandez, D. Auchere et al., Stereoselective efflux in the cerebral transport of mefloquine in mice, American Association of Pharmaceutical Sciences Annual Meeting, pp.26-30, 2003.

S. Retout, E. Comets, and F. Mentré, Comparison between the Fedorov-Wynn and the Simplex algorithm for population design optimisation using a model of the HIV viral load decrease. 13 th meeting of the Population Approach Group in Europe, 2004.

E. Comets, F. Mentré, and F. Gimenez, Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. 13 th meeting of the Population Approach Group in Europe, 2004.

S. Retout, E. Comets, A. Samson, and F. Mentré, Designs in nonlinear mixed effects models : application to HIV viral load decrease with evaluation, optimization and determination of the power of the test of a treatment effect. 14 th meeting of the Population Approach Group in Europe, 2005.

K. Brendel, E. Comets, C. Laveille, C. Laffont, and F. Mentré, Metrics based on objective function for external validation of a population pharmacokinetic model. 14 th meeting of the Population Approach Group in Europe, 2005.

E. Comets, C. Verstuyft, and F. Mentré, Building a pharmacogenetic model to describe the pharmacokinetics of digoxin. 14 th meeting of the Population Approach Group in Europe, 2005.

E. Comets, C. Verstuyft, and A. Mallet, Analysis of digoxin data using Non-Parametric Maximum Likelihood (NPML). 15 th meeting of the Population Approach Group in Europe, 1010.

J. Bertrand, E. Comets, and F. Mentré, Detecting a gene effect in pharmacokinetic models : comparison of different methods. 15 th meeting of the Population Approach Group in Europe, 2006.

C. Miceli-richard, M. Ohresser, E. Comets, P. Goupille, C. Verstuyft et al., Analysis of Fc gamma-receptor IIA, IIIA and IIIB gene polymorphisms as predictive factors of response to adalimumab in rheumatoid arthritis patients treated in the ReAct study, Arthritis and Rheumatism, pp.128-128, 2006.

C. Miceli-richard, C. Verstuyft, E. Comets, P. Loiseau, R. Tamouza et al., Analysis of the shared epitope and selected proand anti-inflammatory cytokine genes polymorphism as predictive factors of response to adalimumab in rheumatoid arthritis patients treated in the ReAct study, Arthritis and Rheumatism, pp.128-129, 2006.

C. Miceli-richard, E. Comets, C. Verstuyft, P. Loiseau, R. Tamouza et al., A single tumor necrosis factor alpha haplotype influences the response to adalimumab in rheumatoid arthritis patients, Arthritis and Rheumatism, p.4038, 2006.

C. Dartois, K. Brendel, E. Comets, C. Laveille, C. Laffont et al., How is model building reported for population PK-PD ? An exhaustive survey of the literature between, 2002.

K. Brendel, C. Dartois, E. Comets, C. Laveille, A. Lemenuel-diot et al., Are population PK/PD models adequately evaluated ? An exhaustive survey of the literature between, 1009.

S. Retout, E. Comets, L. Nagard, H. Mentré, and F. , New features for population designs evaluation and optimisation in R : PFIM 2.0 and PFIMOP 2.0. 15 th meeting of the Population Approach Group in Europe, 1006.

E. Comets, K. Brendel, and F. Mentré, Normalised prediction distribution errors in R : the npde library. 16 th meeting of the Population Approach Group in Europe, 1120.

S. Retout, E. Comets, L. Nagard, H. Mentré, and F. , Population designs evaluation and optimisation in R : the PFIM function and its new features. 16 th meeting of the Population Approach Group in Europe, 1164.

S. Retout, C. Bazzoli, E. Comets, L. Nagard, H. Mentré et al., Population designs evaluation and optimisation in R : the PFIM function and its new features. Population Optimum Design of Experiments : Workshop, Sandwich, United Kingdom, 2007.

K. Brendel, E. Comets, and F. Mentré, Normalised prediction distribution errors for the evaluation of nonlinear mixed-effects models. 16 th meeting of the Population Approach Group in Europe, 1085.

E. Comets and S. Zohar, Modelling is seldom used to describe pharmacokinetics in phase i clinical trials. 17 th meeting of the Population Approach Group in Europe, 1292.

S. Retout, E. Comets, and F. Mentré, Design optimisation in nonlinear mixed effects models using cost functions : application to a joint model of infliximab and methotrexate pharmacokinetics

J. Bertrand, E. Comets, and F. Mentré, Influence of the design on testing the effect of a genetic covariate on pharmacokinetic parameters, with the SAEM algorithm. 17 th meeting of the Population Approach Group in Europe, 1337.

E. Comets, J. Antic, and R. Savic, A bibliographic review of non-parametric methods and their application . 18 th meeting of the Population Approach Group in Europe, 1647.

C. Bazzoli, S. Retout, E. Comets, A. Dubois, L. Nagard et al., New features for population design evaluation and optimization with R functions. 18 th meeting of the Population Approach Group in Europe, 1587.

J. Bertrand, E. Comets, C. Laffont, M. Chesnel, and F. Mentré, Model-based tests to detect gene effect in pharmacokinetic studies. 18 th meeting of the Population Approach Group in Europe, 1464.

D. Bonnet-zamponi, M. Aumont, C. Bruhat, S. Delpierre, M. Chauveheid et al., Fluindione anticoagulation level in very elderly inpatients : the prepa study, Congress of Gerontology, 2009.

. Dans-ces-travaux, nous nous sommes intéressées à la sélection de modèles incluant des covariables génétiques dans les modèles pharmacocinétiques. Les covariables génétiques ont certaines spécificités : les mutations ponctuelles sur un gène (appelées SNP, pour single nucleotide polymorphism) génèrent un génotype qui peut être traité comme une covariable en plusieurs classes. Dans le cas d'un polymorphisme biallélique, 3 phénotypes se présentent (type sauvage, hétérozygote mutant, ou homozygote mutant) ; leur distribution dans la population est souvent fortement déséquilibrée et généralement non maîtrisable

. Cet-essai-multicentrique, égide de l'agence nationale pour la recherche sur le SIDA, étudiait le bénéfice de l'adaptation précoce des doses d'anti-rétroviraux, chez des patients VIH naïfs, après la mesure de concentrations résiduelles des inhibiteurs de protéase. Nous avons analysé le bras indinavir de cette étude, où 40 patients ont reçu de l'indinavir de façon chronique

. Dans-un, nous avons évalué trois tests classiques utilisés en pharmacocinétique pour la construction de modèles : le test du rapport de vraisemblance comparant le modèle avec et sans la Emmanuelle Comets Mémoire, 2010.