Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients.
Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes.



Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models.



The bevacizumab volume of distribution increased with height (p = 10-10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively).



High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.
Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.|Department of Gastroenterology, CHRU de Tours, Tours, France.
Morgane
M
Caulet
Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.|Department of Gastroenterology, CHRU de Tours, Tours, France.
Thierry
T
Lecomte
Department of Gastroenterology and Digestive Oncology, CHU de Reims, Reims, France.
Olivier
O
Bouché
Department of Gastroenterology, CHRU de Tours, Tours, France.|Laboratory of Haematology-Haemostasis, CHU de Tours, Tours, France.
Jérôme
J
Rollin
Department of Gastroenterology, CHRU de Tours, Tours, France.|Laboratory of Immunology, CHU de Tours, Tours, France.
Valérie
V
Gouilleux-Gruart
Department of Gastroenterology, CHRU de Tours, Tours, France.
Nicolas
N
Azzopardi
INSERM CIC 1415, CHU de Tours, Tours, France.
Julie
J
Léger
Department of Oncology, CHU Besançon, Besançon, France.
Christophe
C
Borg
Centre René Gauducheau, Institut de Cancerologie, Nantes, France.
Jean-Yves
JY
Douillard
Department of Gastroenterology, CHU de Rennes, Rennes, France.
Sylvain
S
Manfredi
Department of Oncology, CHU de Bordeaux, Bordeaux, France.
Denis
D
Smith
Department of Medical Oncology, ICO, Angers, France.
Olivier
O
Capitain
Department of Medical Oncology, CHU de Poitiers, Poitiers, France.
Aurélie
A
Ferru
Department of Gastroenterology, CHRU de Tours, Tours, France.
Driffa
D
Moussata
Department of Gastroenterology, CHU de Bordeaux, Bordeaux, France.
Eric
E
Terrebone
Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.|Laboratoire de pharmacologie-toxicologie, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France.
Gilles
G
Paintaud
Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. david.ternant@univ-tours.fr.|Laboratoire de pharmacologie-toxicologie, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.
David
D
Ternant
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D002272:Carcinoembryonic Antigen; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab