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.
Eppler
Stephen M
SM
Clinical and Experimental Pharmacology Department, the Bioanalytical Assays Department, and the Medical Affairs Department, Genentech, South San Francisco, CA 94080, USA.
Combs
Daniel L
DL
Henry
Timothy D
TD
Lopez
John J
JJ
Ellis
Stephen G
SG
Yi
Joo-Hee
JH
Annex
Brian H
BH
McCluskey
Edward R
ER
Zioncheck
Thomas F
TF
D000328:Adult; D000368:Aged; D003327:Coronary Disease / Q000503:physiopathology; D003331:Coronary Vessels; D016228:Endothelial Growth Factors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008222:Lymphokines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors