The Vascular Endothelial Growth Factor (VEGF) in Ischemiafor Vascular Angiogenesis (VIVA) trial was a double‐blind, placebo‐controlled, phase II clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of combinedintracoronary and intravenous infusions of recombinant human vascular endothelial growth factor (rhVEGF₁₆₅) for therapeutic angiogenesis. This study describes the use of a mechanism‐based model to characterize the nonlinear kinetics observed after intravenous administration of rhVEGF₁₆₅. The model predicts that rhVEGF₁₆₅ distribution occurs through both saturable binding to high‐affinity receptors and reversible interactions with low‐affinity binding sites.

In this trial, rhVEGF₁₆₅ 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.

The plasma clearance, steady‐state volume of distribution, and terminal half‐life after a 4‐hour intravenous infusion of rhVEGF₁₆₅ 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 rhVEGF₁₆₅ administration appeared to be related to the model‐predicted VEGF₁₆₅ concentration associated with the high‐affinity receptor compartment.

This mechanism‐based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF₁₆₅ dose regimens that may aid in optimization of drug delivery for future clinical trials.

Clinical Pharmacology & Therapeutics (2002) 72, 20–32; doi: 10.1067/mcp.2002.126179