title: Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer.
abstract: OBJECTIVE
  Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab.
  
  
  METHODS
  Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4 mg kg(-1) loading dose followed by 5 weekly 2 mg kg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate.
  
  
  RESULTS
  A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1 l (23%), peripheral volume of distribution =1.3 l (38%), intercompartment clearance =0.36 l day(-1) , with an elimination half-life of 11.8 days. Typical clearance was 0.22 l day(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size.
  
  
  CONCLUSIONS
  In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied.
authors.affiliation: CNRS, UMR 7292, « Genetics, Immunotherapy, Chemistry and Cancer », Université François Rabelais de Tours, Tours.|CHRU de Tours, Clinique d'Oncologie et de Radiothérapie, Tours.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Bernadou
authors.affiliation: Department of Medical Oncology/Cancer Research Center UMR-INSERM, U892/CNRS 6299/Bioinformatics Unit, Institut de Cancérologie de l'Ouest, Nantes.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Faculté de Pharmacie, Université de Lorraine, Nancy.|CNRS UMR7039 CRAN, Vandoeuvre les Nancy.|Service de Biopathologie, Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.affiliation: CNRS, UMR 7292, « Genetics, Immunotherapy, Chemistry and Cancer », Université François Rabelais de Tours, Tours.|CHRU de Tours, Service d'Immunologie, Tours.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, INSERM U1052, Lyon.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Department of Radiopharmacology, Institut Curie-René Huguenin Hospital, Saint-Cloud.
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.affiliation: Department of Radiopharmacology, Institut Curie-René Huguenin Hospital, Saint-Cloud.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Rezai
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif.
authors.forename: Monica
authors.initials: M
authors.lastname: Arnedos
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: R&D Unicancer, UNICANCER, Paris.
authors.forename: Marta
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: CNRS, UMR 7292, « Genetics, Immunotherapy, Chemistry and Cancer », Université François Rabelais de Tours, Tours.|CHRU de Tours, Laboratoire de Pharmacologie-Toxicologie, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: CNRS, UMR 7292, « Genetics, Immunotherapy, Chemistry and Cancer », Université François Rabelais de Tours, Tours.|CHRU de Tours, Laboratoire de Pharmacologie-Toxicologie, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000068338:Everolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047368:Tumor Burden; D016217:Ultrasonography, Mammary
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: breast cancer; pharmacokinetics; population PK modelling; trastuzumab