Guillemette Bernadou1,2, Mario Campone3, Jean-Louis Merlin4,5,6, Valérie Gouilleux-Gruart1,7, Thomas Bachelot8, François Lokiec9, Keyvan Rezai9, Monica Arnedos10, Véronique Diéras10, Marta Jimenez11, Gilles Paintaud1,12, David Ternant1,12. 1. CNRS, UMR 7292, « Genetics, Immunotherapy, Chemistry and Cancer », Université François Rabelais de Tours, Tours. 2. CHRU de Tours, Clinique d'Oncologie et de Radiothérapie, Tours. 3. Department of Medical Oncology/Cancer Research Center UMR-INSERM, U892/CNRS 6299/Bioinformatics Unit, Institut de Cancérologie de l'Ouest, Nantes. 4. Faculté de Pharmacie, Université de Lorraine, Nancy. 5. CNRS UMR7039 CRAN, Vandoeuvre les Nancy. 6. Service de Biopathologie, Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy. 7. CHRU de Tours, Service d'Immunologie, Tours. 8. Department of Medical Oncology, Centre Léon Bérard, INSERM U1052, Lyon. 9. Department of Radiopharmacology, Institut Curie-René Huguenin Hospital, Saint-Cloud. 10. Department of Medical Oncology, Gustave Roussy, Villejuif. 11. R&D Unicancer, UNICANCER, Paris. 12. CHRU de Tours, Laboratoire de Pharmacologie-Toxicologie, Tours, France.
Abstract
AIMS: 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.
RCT Entities:
AIMS: 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 cancerpatients 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 cancerpatients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancerpatients previously studied.
Authors: Angelica L Quartino; Hanbin Li; Whitney P Kirschbrown; Ranvir Mangat; D Russell Wada; Amit Garg; Jin Y Jin; Bert Lum Journal: Cancer Chemother Pharmacol Date: 2018-11-22 Impact factor: 3.333
Authors: Imke H Bartelink; Ella F Jones; Sheerin K Shahidi-Latham; Pei Rong Evelyn Lee; Yanan Zheng; Paolo Vicini; Laura van 't Veer; Denise Wolf; Andrei Iagaru; Deanna L Kroetz; Brendan Prideaux; Cornelius Cilliers; Greg M Thurber; Zena Wimana; Geraldine Gebhart Journal: Clin Pharmacol Ther Date: 2018-10-06 Impact factor: 6.875
Authors: E Krasniqi; G Barchiesi; L Pizzuti; M Mazzotta; A Venuti; M Maugeri-Saccà; G Sanguineti; G Massimiani; D Sergi; S Carpano; P Marchetti; S Tomao; T Gamucci; R De Maria; F Tomao; C Natoli; N Tinari; G Ciliberto; M Barba; P Vici Journal: J Hematol Oncol Date: 2019-10-29 Impact factor: 17.388