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

Autor: Stephen Eppler, Stephen G. Ellis, Daniel L. Combs, Timothy D. Henry, Joo Hee Yi, Brian H. Annex, Edward R. McCluskey, John J. Lopez, Thomas F. Zioncheck
Rok vydání: 2002
Předmět:
Zdroj: Clinical Pharmacology & Therapeutics. 72:20-32
ISSN: 1532-6535
0009-9236
Popis: Background 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. Methods 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. Results 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. Conclusions 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
Databáze: OpenAIRE
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