R. 1. Evans, W. Relling, M. Rodman, and J. , Conventional Compared with Individualized Chemotherapy for Childhood Acute Lymphoblastic Leukemia, New England Journal of Medicine, vol.338, issue.8, pp.499-505, 1998.
DOI : 10.1056/NEJM199802193380803

D. Jodrell, M. Egorin, and R. Canetta, Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer., Journal of Clinical Oncology, vol.10, issue.4, pp.520-528, 1992.
DOI : 10.1200/JCO.1992.10.4.520

H. Kastrissios and M. Ratain, Screening for Sources of Interindividual Pharmacokinetic Variability in Anticancer Drug Therapy: Utility of Population Analysis, Cancer Investigation, vol.16, issue.1, pp.57-64, 2001.
DOI : 10.1007/s002800050256

R. Lancelot and M. Lesnoff, Sélection des modèles avec l'AIC et critères d'informations dérivés, Cirad, Montpellier. Cirad, vol.10, pp.1-7, 2005.

A. Felici, J. Verweij, and A. Sparreboom, Dosing strategies for anticancer drugs: the good, the bad and body-surface area, European Journal of Cancer, vol.38, issue.13, pp.1677-1684, 2002.
DOI : 10.1016/S0959-8049(02)00151-X

M. Gottesman, T. Fojo, and S. Bates, MULTIDRUG RESISTANCE IN CANCER: ROLE OF ATP-DEPENDENT TRANSPORTERS, Nature Reviews Cancer, vol.2, issue.1, pp.48-58, 2002.
DOI : 10.1038/nrc706

S. Wrighton, M. Vandenbranden, and B. Ring, The human drug metabolizing cytochromes P450, Journal of Pharmacokinetics and Biopharmaceutics, vol.22, issue.5, pp.461-473, 1996.
DOI : 10.1007/BF02353474

P. Canal and E. Chatelut, Dose optimization in clinical oncology: pharmacokineticpharmacodynamic relationship], Bull Cancer, vol.83, pp.256-265, 1996.

C. Scripture and W. Figg, Drug interactions in cancer therapy, Nature Reviews Cancer, vol.17, issue.7, pp.546-558, 2006.
DOI : 10.1038/nrc1887

R. Noble, The discovery of the vinca alkaloids???chemotherapeutic agents against cancer, Biochemistry and Cell Biology, vol.68, issue.12, pp.1344-1351, 1990.
DOI : 10.1139/o90-197

D. Leveque, J. Wihlm, and F. Jehl, Pharmacology of Catharanthus alkaloids], Bull Cancer, vol.83, pp.176-186, 1996.

J. Johnson, J. Armstronf, G. M. Burnett, and J. , The vinca alkaloids: a new class of oncolytic agents, Cancer Res, vol.23, pp.1390-1427, 1963.

M. Sweeney, G. Boder, and G. Cullinan, Antitumor activity of deacetyl vinblastine amide sulfate (vindesine) in rodents and mitotic accumulation studies in culture, Cancer Res, vol.38, pp.2886-2891, 1978.

F. Gueritte, A. Pouilhe, and P. Mangeney, Synthesis of navelbine analogs, Eut J Med Chem, vol.10, pp.419-424, 1983.

T. Delozier, J. Guastalla, and A. Yovine, A phase II study of an oxaliplatin/vinorelbine/5-fluorouracil combination in patients with anthracycline-pretreated and taxane-pretreated metastatic breast cancer, Anti-Cancer Drugs, vol.17, issue.9, pp.1067-1073, 2006.
DOI : 10.1097/01.cad.0000231475.77159.aa

J. Bennouna, J. Delord, M. Campone, and L. Nguyen, Vinflunine: A New Microtubule Inhibitor Agent, Clinical Cancer Research, vol.14, issue.6, pp.1625-1632, 2008.
DOI : 10.1158/1078-0432.CCR-07-2219

S. Binet, A. Fellous, and H. Lataste, In situ analysis of the action of Navelbine on various types of microtubules using immunofluorescence, Semin Oncol, vol.16, pp.5-8, 1989.

A. Fellous, R. Luduena, and V. Prasad, Effects of Tau and MAP2 on the interaction of maytansine with tubulin: inhibitory effect of maytansine on vinblastine-induced aggregation of tubulin, Cancer Res, vol.45, pp.5004-5010, 1985.

M. Besenval, M. Delgado, J. Demarez, and A. Krikorian, Safety and tolerance of Navelbine in phase I-II clinical studies, Semin Oncol, vol.16, pp.37-40, 1989.

R. Nelson, R. Dyke, and M. Root, Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer, Cancer Treatment Reviews, vol.7, issue.1, pp.17-24, 1980.
DOI : 10.1016/S0305-7372(80)80003-X

R. Rahmani, R. Bruno, and A. Iliadis, Clinical pharmacokinetics of the antitumor drug navelbine (5'-noranhydrovinblastine), Cancer Res, vol.47, pp.5796-5799, 1987.

F. Jehl, E. Quoix, and D. Leveque, Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography, Cancer Res, vol.51, pp.2073-2076, 1991.

D. Khayat, O. Rixe, and R. Brunet, Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design, Cancer Chemotherapy and Pharmacology, vol.54, issue.3, pp.193-205, 2004.
DOI : 10.1007/s00280-004-0794-1

C. Sabot, P. Marquet, and J. Debord, Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients, European Journal of Clinical Pharmacology, vol.54, issue.2, pp.171-175, 1998.
DOI : 10.1007/s002280050441

A. Gauvin, F. Pinguet, and S. Culine, Blood and plasma pharmacokinetics of vinorelbine in elderly patients with advanced metastatic cancer, Cancer Chemotherapy and Pharmacology, vol.49, issue.1, pp.48-56, 2002.
DOI : 10.1007/s00280-001-0378-2

S. Urien, F. Bree, and F. Breillout, Vinorelbine high-affinity binding to human platelets and lymphocytes: distribution in human blood, Cancer Chemotherapy and Pharmacology, vol.28, issue.3, pp.231-234, 1993.
DOI : 10.1007/BF00685841

D. Leveque and F. Jehl, Clinical Pharmacokinetics of Vinorelbine, Clinical Pharmacokinetics, vol.31, issue.3, pp.184-197, 1996.
DOI : 10.2165/00003088-199631030-00003

M. Marty, P. Fumoleau, and A. Adenis, Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors, Annals of Oncology, vol.12, issue.11, pp.1643-1649, 2001.
DOI : 10.1023/A:1013180903805

D. Beulz-riche, P. Grude, and C. Puozzo, Characterization of human cytochrome P450 isoenzymes involved in the metabolism of vinorelbine, Fundamental and Clinical Pharmacology, vol.28, issue.5, pp.545-553, 2005.
DOI : 10.1006/abio.1976.9999

B. Wroblewski and M. Glenn, The Cytochrome P-450 Drug Metabolizing Enzyme System, Journal of Head Trauma Rehabilitation, vol.17, issue.6, pp.571-574, 2002.
DOI : 10.1097/00001199-200212000-00008

K. Kivisto, H. Kroemer, and M. Eichelbaum, The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions., British Journal of Clinical Pharmacology, vol.14, issue.6, pp.523-530, 1995.
DOI : 10.1111/j.1365-2125.1995.tb05796.x

W. Evans and M. Relling, Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics, Science, vol.286, issue.5439, pp.487-491, 1999.
DOI : 10.1126/science.286.5439.487

M. Cotreau, L. Von-moltke, and D. Greenblatt, The Influence of Age and Sex on the Clearance of Cytochrome P450 3A Substrates, Clinical Pharmacokinetics, vol.308, issue.1, pp.33-60, 2005.
DOI : 10.2165/00003088-200544010-00002

J. Kajita, T. Kuwabara, H. Kobayashi, and S. Kobayashi, CYP3A4 is mainly responsibile for the metabolism of a new vinca alkaloid, vinorelbine, in human liver microsomes, Drug Metab Dispos, vol.28, pp.1121-1127, 2000.

D. Adams and V. Knick, P-Glycoprotein mediated resistance to 5???-nor-anhydro-vinblastine (Navelbine??), Investigational New Drugs, vol.67, issue.5B, pp.13-21, 1995.
DOI : 10.1007/BF02614215

A. Krikorian, R. Rahmani, and M. Bromet, Pharmacokinetics and metabolism of Navelbine, Semin Oncol, vol.16, pp.21-25, 1989.

L. Nguyen, B. Tranchand, C. Puozzo, and P. Variol, Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials, British Journal of Clinical Pharmacology, vol.38, issue.5, pp.459-468, 2002.
DOI : 10.1046/j.1365-2125.2002.01581.x

P. Variol, L. Nguyen, B. Tranchand, and C. Puozzo, A simultaneous oral/intravenous population pharmacokinetic model for vinorelbine, European Journal of Clinical Pharmacology, vol.58, issue.7, pp.467-476, 2002.
DOI : 10.1007/s00228-002-0506-x

I. Robieux, R. Sorio, and E. Borsatti, Pharmacokinetics of vinorelbine in patients with liver metastases, Clinical Pharmacology & Therapeutics, vol.13, issue.1, pp.32-40, 1996.
DOI : 10.1016/S0009-9236(96)90021-1

L. Klapper, M. Kirschbaum, M. Sela, and Y. Yarden, Biochemical and Clinical Implications of the ErbB/HER Signaling Network of Growth Factor Receptors, Adv Cancer Res, vol.77, pp.25-79, 2000.
DOI : 10.1016/S0065-230X(08)60784-8

G. Atalay, F. Cardoso, A. Awada, and M. Piccart, Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer, Annals of Oncology, vol.14, issue.9, pp.1346-1363, 2003.
DOI : 10.1093/annonc/mdg365

B. Moy and P. Goss, Lapatinib: Current Status and Future Directions in Breast Cancer, The Oncologist, vol.11, issue.10, pp.1047-1057, 2006.
DOI : 10.1634/theoncologist.11-10-1047

M. Janmaat and G. Giaccone, Small-Molecule Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, The Oncologist, vol.8, issue.6, pp.576-586, 2003.
DOI : 10.1634/theoncologist.8-6-576

R. Nahta, L. Yuan, Y. Du, and F. Esteva, Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling, Molecular Cancer Therapeutics, vol.6, issue.2, pp.667-674, 2007.
DOI : 10.1158/1535-7163.MCT-06-0423

C. Geyer, J. Forster, and D. Lindquist, Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer, New England Journal of Medicine, vol.355, issue.26, pp.2733-2743, 2006.
DOI : 10.1056/NEJMoa064320

W. Xia, L. Liu, P. Ho, and N. Spector, Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016, Oncogene, vol.23, issue.3, pp.646-653, 2004.
DOI : 10.1038/sj.onc.1207166

B. Moy and P. Goss, Lapatinib-Associated Toxicity and Practical Management Recommendations, The Oncologist, vol.12, issue.7, pp.756-765, 2007.
DOI : 10.1634/theoncologist.12-7-756

M. Nelson and C. Dolder, Lapatinib: A Novel Dual Tyrosine Kinase Inhibitor with Activity in Solid Tumors, Annals of Pharmacotherapy, vol.29, issue.3, pp.261-269, 2006.
DOI : 10.1345/aph.1G387

D. Smith, K. Koch, and N. Arya, Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects, British Journal of Clinical Pharmacology, vol.76, issue.4, pp.421-426, 2009.
DOI : 10.1111/j.1365-2125.2009.03370.x

B. Thiessen, C. Stewart, and M. Tsao, A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation, Cancer Chemotherapy and Pharmacology, vol.64, issue.2, pp.353-361, 2010.
DOI : 10.1007/s00280-009-1041-6

K. Koch, N. Reddy, and R. Cohen, Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients, Journal of Clinical Oncology, vol.27, issue.8, pp.1191-1196, 2009.
DOI : 10.1200/JCO.2008.18.3285

J. Polli, J. Humphreys, and K. Harmon, The Role of Efflux and Uptake Transporters in N-??-6-[5-(??methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions, Drug Metabolism and Disposition, vol.36, issue.4, pp.695-701, 2008.
DOI : 10.1124/dmd.107.018374

S. Castellino, O. Mara, M. Koch, and K. , Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity, Drug Metabolism and Disposition, vol.40, issue.1, 2011.
DOI : 10.1124/dmd.111.040949

W. Teng, J. Oh, and L. New, Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib, Molecular Pharmacology, vol.78, issue.4, pp.693-703, 2010.
DOI : 10.1124/mol.110.065839

A. Parkinson, An Overview of Current Cytochrome P450 Technology for Assessing the Safety and Efficacy of New Materials, Toxicologic Pathology, vol.24, issue.1, pp.48-57, 1996.
DOI : 10.1177/019262339602400107

J. Jones, A. Takeda, and J. Picot, Lapatinib for the treatment of HER2-overexpressing breast cancer, Health Technology Assessment, vol.13, issue.Suppl 3, pp.1-6, 2009.
DOI : 10.3310/hta13suppl3/01

R. Nahta and F. Esteva, HER2 therapy: Molecular mechanisms of trastuzumab resistance, Breast Cancer Research, vol.62, issue.Suppl, p.215, 2006.
DOI : 10.1158/1078-0432.CCR-05-0344

J. Van-heugen, D. Graeve, J. Zorza, G. Puozzo, and C. , New sensitive liquid chromatography method coupled with tandem mass spectrometric detection for the clinical analysis of vinorelbine and its metabolites in blood, plasma, urine and faeces, Journal of Chromatography A, vol.926, issue.1, pp.11-20, 2001.
DOI : 10.1016/S0021-9673(01)00993-1

F. Bai, B. Freeman, I. Fraga, and C. , Determination of lapatinib (GW572016) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC???ESI-MS/MS), Journal of Chromatography B, vol.831, issue.1-2, pp.169-175, 2006.
DOI : 10.1016/j.jchromb.2005.11.044

L. Sheiner, The Population Approach to Pharmacokinetic Data Analysis: Rationale and Standard Data Analysis Methods, Drug Metabolism Reviews, vol.27, issue.1-2, pp.153-171, 1984.
DOI : 10.1214/aoms/1177706645

M. Karlsson and L. Sheiner, The importance of modeling interoccasion variability in population pharmacokinetic analyses, Journal of Pharmacokinetics and Biopharmaceutics, vol.32, issue.6, pp.735-750, 1993.
DOI : 10.1007/BF01113502

E. Kuhn and M. Lavielle, Maximum likelihood estimation in nonlinear mixed effects models, Computational Statistics & Data Analysis, vol.49, issue.4, pp.1020-1030, 2005.
DOI : 10.1016/j.csda.2004.07.002

M. Lavielle and F. Mentre, Estimation of Population Pharmacokinetic Parameters of Saquinavir in HIV Patients with the MONOLIX Software, Journal of Pharmacokinetics and Pharmacodynamics, vol.32, issue.2, pp.229-249, 2007.
DOI : 10.1007/s10928-006-9043-z

URL : https://hal.archives-ouvertes.fr/inserm-00156907

A. Gauvin, F. Pinguet, and S. Culine, Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer, Clin Cancer Res, vol.6, pp.2690-2695, 2000.

M. Wong, R. Balleine, and E. Blair, Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer, Journal of Clinical Oncology, vol.24, issue.16, pp.2448-2455, 2006.
DOI : 10.1200/JCO.2005.02.1295

E. Ette and T. Ludden, Population pharmacokinetic modeling: the importance of informative graphics, Pharmaceutical Research, vol.12, issue.12, pp.1845-1855, 1995.
DOI : 10.1023/A:1016215116835

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.154-166, 2008.
DOI : 10.1016/j.cmpb.2007.12.002

URL : https://hal.archives-ouvertes.fr/inserm-00274332

H. Akaike, A new look at statistacal model identification, IEEE Transactions TAC, vol.19, pp.716-722, 1974.

D. Baerdemaeker, L. Mortier, E. Struys, and M. , Pharmacokinetics in obese patients, Continuing Education in Anaesthesia, Critical Care & Pain, vol.4, issue.5, pp.152-157, 2004.
DOI : 10.1093/bjaceaccp/mkh042

Y. Yano, S. Beal, and L. Sheiner, Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check, Journal of Pharmacokinetics and Pharmacodynamics, vol.28, issue.2, pp.171-192, 2001.
DOI : 10.1023/A:1011555016423

L. Friberg, A. Henningsson, and H. Maas, Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs, Journal of Clinical Oncology, vol.20, issue.24, pp.4713-4721, 2002.
DOI : 10.1200/JCO.2002.02.140

D. Harrison and C. Lerner, Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil, Blood, vol.78, pp.1237-1240, 1991.

N. Testa and E. Tuddenham, The regulation of haematopoietic cell production, Postgraduate Haematol, vol.4, pp.1-12, 1999.

H. Takatani, H. Soda, and M. Fukuda, Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts, Antimicrob Agents Chemother, vol.40, pp.988-991, 1996.

M. Simeoni, P. Magni, and C. Cammia, Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Kinetics in Xenograft Models after Administration of Anticancer Agents, Cancer Research, vol.64, issue.3, pp.1094-1101, 2004.
DOI : 10.1158/0008-5472.CAN-03-2524

L. Claret, P. Girard, and P. Hoff, Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics, Journal of Clinical Oncology, vol.27, issue.25, pp.4103-4108, 2009.
DOI : 10.1200/JCO.2008.21.0807

E. Eisenhauer, P. Therasse, and J. Bogaerts, New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), European Journal of Cancer, vol.45, issue.2, pp.228-247, 2009.
DOI : 10.1016/j.ejca.2008.10.026

P. Therasse, S. Arbuck, and E. Eisenhauer, New Guidelines to Evaluate the Response to Treatment in Solid Tumors, JNCI: Journal of the National Cancer Institute, vol.92, issue.3, pp.205-216, 2000.
DOI : 10.1093/jnci/92.3.205

K. Rezai, S. Urien, and N. Isambert, Pharmacokinetic evaluation of the vinorelbine???lapatinib combination in the treatment of breast cancer patients, Cancer Chemotherapy and Pharmacology, vol.65, issue.Suppl 4, pp.1529-1536, 2011.
DOI : 10.1007/s00280-011-1650-8

K. Rezai, N. Isambert, and E. Brain, GEP01: a phase pharmacokinetic study of lapatinib and iv vinorelbine in the treatment of HER2-positive locally advanced or metastatic breast cancer, Poster AACR, vol.10, p.850, 2011.

K. Rezai, F. Lokiec, and E. Brain, Population pharmacokinetic pharmacodynamic model for neutropenia and tumor shrinkage time course by vinorelbine-lapatinib combination in breast cancer patients, Clin Cancer Res, vol.Soumis:, 2011.

S. Undevia, G. Gomez-abuin, and M. Ratain, Pharmacokinetic variability of anticancer agents, Nature Reviews Cancer, vol.7, issue.6, pp.447-458, 2005.
DOI : 10.1016/0002-9343(86)90718-7

E. Ette and P. Williams, Population Pharmacokinetics I: Background, Concepts, and Models, Annals of Pharmacotherapy, vol.32, issue.10, pp.1702-1706, 2004.
DOI : 10.1007/978-1-4613-3255-8_15

E. Samara and R. Granneman, Role of Population Pharmacokinetics in Drug Development, Clinical Pharmacokinetics, vol.32, issue.4, pp.294-303, 1997.
DOI : 10.2165/00003088-199732040-00003

E. Brain, N. Isambert, and F. Dalenc, Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2, British Journal of Cancer, vol.44, issue.4, 2011.
DOI : 10.1038/bjc.2011.591

R. Urso, C. Nencini, G. Giorgi, and A. Fiaschi, Chemotherapy-induced myelosuppression by vinorelbine: a comparison between different dose schedules by simulation, Eur Rev Med Pharmacol Sci, vol.11, pp.413-417, 2007.

C. Kloft, W. Siegert, and U. Jaehde, Individualised dosing strategy for high-dose carboplatin in patients with germ cell cancer, British Journal of Cancer, vol.89, issue.5, pp.787-794, 2003.
DOI : 10.1038/sj.bjc.6601215

M. Sandstrom, H. Lindman, and P. Nygren, Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients, Cancer Chemotherapy and Pharmacology, vol.55, issue.24, pp.143-156, 2006.
DOI : 10.1007/s00280-005-0140-2

D. Newell, Can pharmacokinetic and pharmacodynamic studies improve cancer chemotherapy?, Annals of Oncology, vol.5, issue.suppl 4, pp.9-15, 1994.
DOI : 10.1093/annonc/5.suppl_4.S9

URL : http://annonc.oxfordjournals.org/cgi/content/short/5/suppl_4/S9