title: Effects of anti-VEGF on predicted antibody biodistribution: roles of vascular volume, interstitial volume, and blood flow.
abstract: BACKGROUND
  The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences.
  
  
  RESULTS
  Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice.
  
  
  CONCLUSIONS
  These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
authors: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, United States of America. boswell.andy@gene.com
authors: C Andrew
authors: CA
authors: Boswell
authors: Gregory Z
authors: GZ
authors: Ferl
authors: Eduardo E
authors: EE
authors: Mundo
authors: Daniela
authors: D
authors: Bumbaca
authors: Michelle G
authors: MG
authors: Schweiger
authors: Frank-Peter
authors: FP
authors: Theil
authors: Paul J
authors: PJ
authors: Fielder
authors: Leslie A
authors: LA
authors: Khawli
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001808:Blood Vessels / Q000187:drug effects*; D002458:Cell Fractionation; D003198:Computer Simulation; D004912:Erythrocytes / Q000000981:diagnostic imaging / Q000187:drug effects; D018056:Hemorheology / Q000187:drug effects*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D013667:Technetium; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; D042442:Vascular Endothelial Growth Factors; D013667:Technetium