Effects of anti-VEGF on predicted antibody biodistribution: roles of vascular volume, interstitial volume, and blood flow

• Published in: PloS one 2011-03, Vol.6 (3), p.e17874
• Main Authors: Boswell, C Andrew, Ferl, Gregory Z, Mundo, Eduardo E, Bumbaca, Daniela, Schweiger, Michelle G, Theil, Frank-Peter, Fielder, Paul J, Khawli, Leslie A
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animal tissues; Animals; Antibodies; Antibodies - administration & dosage; Antibodies - pharmacology; Antigens; Area Under Curve; Biology; Blood; Blood flow; Blood Vessels - drug effects; Cancer; Cell Fractionation; Chemistry; Computed tomography; Computer Simulation; Drug delivery systems; Drug development; Drugs; Emission analysis; Erythrocytes - diagnostic imaging; Erythrocytes - drug effects; Flow velocity; Glycoproteins; Hemorheology - drug effects; Immunoglobulins; Immunology; Indium; Intravenous administration; Kinetics; Mathematical models; Medicine; Melanoma; Mice; Organ Size - drug effects; Permeability; Pharmaceuticals; Pharmacology; Photon emission; Physiological aspects; Physiology; Plasma; Prediction models; Quantitative analysis; Radiochemistry; Radioisotopes; Regional Blood Flow - drug effects; Rubidium; Studies; Technetium; Therapeutics; Tissue Distribution - drug effects; Tomography; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factors - antagonists & inhibitors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017874

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. 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. 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.