A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans

Background: The Vascular Endothelial Growth Factor (VEGF) in Ischemia for Vascular Angiogenesis (VIVA) trial was a double-blind, placebo-controlled, phase II clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of combined intracoronary and intravenous infusions of recombinant human vascular endothelial growth factor (rhVEGF ₁₆₅) for therapeutic angiogenesis. This study describes the use of a mechanism-based model to characterize the nonlinear kinetics observed after intravenous administration of rhVEGF ₁₆₅. The model predicts that rhVEGF ₁₆₅ distribution occurs through both saturable binding to high-affinity receptors and reversible interactions with low-affinity binding sites. Methods: In this trial, rhVEGF ₁₆₅ was administered to patients with coronary artery disease at a dose rate of 17 or 50 ng/kg/min by means of intracoronary infusion for 20 minutes, followed by three 4-hour intravenous infusions on days 3, 6, and 9. Pharmacokinetic samples and blood pressure measurements were collected at baseline, during infusion, and for 6 hours after infusion. Results: The plasma clearance, steady-state volume of distribution, and terminal half-life after a 4-hour intravenous infusion of rhVEGF ₁₆₅ at the high dose were 19.1 ± 5.7 mL/min/kg, 960 ± 260 mL/kg, and 33.7 ± 13 minutes, respectively. The duration of hypotension that occurred after rhVEGF ₁₆₅ administration appeared to be related to the model-predicted VEGF ₁₆₅ concentration associated with the high-affinity receptor compartment. Conclusions: This mechanism-based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF ₁₆₅ dose regimens that may aid in optimization of drug delivery for future clinical trials.