Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients

• Published in: Clinical pharmacokinetics 2016-11, Vol.55 (11), p.1381-1394
• Main Authors: Caulet, Morgane, Lecomte, Thierry, Bouché, Olivier, Rollin, Jérôme, Gouilleux-Gruart, Valérie, Azzopardi, Nicolas, Léger, Julie, Borg, Christophe, Douillard, Jean-Yves, Manfredi, Sylvain, Smith, Denis, Capitain, Olivier, Ferru, Aurélie, Moussata, Driffa, Terrebone, Eric, Paintaud, Gilles, Ternant, David
• Format: Article
• Language: English
• Subjects: Aged; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Bevacizumab - pharmacokinetics; Bevacizumab - pharmacology; Bevacizumab - therapeutic use; Carcinoembryonic Antigen - metabolism; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Human health and pathology; Humans; Hépatology and Gastroenterology; Internal Medicine; Life Sciences; Liver Neoplasms - secondary; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Original Research Article; Pharmaceutical sciences; Pharmacology; Pharmacology/Toxicology; Pharmacotherapy; Polymorphism, Genetic; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-016-0406-3

Objective 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. Methods 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. Results 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). Conclusion High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.