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

Stephen M. Eppler, Daniel L. Combs, Timothy D. Henry, John J. Lopez, Stephen G. Ellis, Joo Hee Yi, Brian H. Annex, Edward R. McCluskey, Thomas F. Zioncheck

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20-32
Number of pages13
JournalClinical Pharmacology and Therapeutics
Volume72
Issue number1
DOIs
StatePublished - Aug 12 2002
Externally publishedYes

Fingerprint

Intravenous Infusions
Pharmacokinetics
Hemodynamics
Vascular Endothelial Growth Factor A
Phase II Clinical Trials
Intravenous Administration
Hypotension
Blood Vessels
Half-Life
Coronary Artery Disease
Ischemia
Binding Sites
Placebos
Clinical Trials
Blood Pressure
Safety
Pharmaceutical Preparations
human VEGFA protein
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. / Eppler, Stephen M.; Combs, Daniel L.; Henry, Timothy D.; Lopez, John J.; Ellis, Stephen G.; Yi, Joo Hee; Annex, Brian H.; McCluskey, Edward R.; Zioncheck, Thomas F.

In: Clinical Pharmacology and Therapeutics, Vol. 72, No. 1, 12.08.2002, p. 20-32.

Research output: Contribution to journalArticle

Eppler, Stephen M. ; Combs, Daniel L. ; Henry, Timothy D. ; Lopez, John J. ; Ellis, Stephen G. ; Yi, Joo Hee ; Annex, Brian H. ; McCluskey, Edward R. ; Zioncheck, Thomas F. / A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. In: Clinical Pharmacology and Therapeutics. 2002 ; Vol. 72, No. 1. pp. 20-32.
@article{de3c3f4c2e5246ce9af67fb39f647366,
title = "A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans",
abstract = "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.",
author = "Eppler, {Stephen M.} and Combs, {Daniel L.} and Henry, {Timothy D.} and Lopez, {John J.} and Ellis, {Stephen G.} and Yi, {Joo Hee} and Annex, {Brian H.} and McCluskey, {Edward R.} and Zioncheck, {Thomas F.}",
year = "2002",
month = "8",
day = "12",
doi = "10.1067/mcp.2002.126179",
language = "English (US)",
volume = "72",
pages = "20--32",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans

AU - Eppler, Stephen M.

AU - Combs, Daniel L.

AU - Henry, Timothy D.

AU - Lopez, John J.

AU - Ellis, Stephen G.

AU - Yi, Joo Hee

AU - Annex, Brian H.

AU - McCluskey, Edward R.

AU - Zioncheck, Thomas F.

PY - 2002/8/12

Y1 - 2002/8/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0036331674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036331674&partnerID=8YFLogxK

U2 - 10.1067/mcp.2002.126179

DO - 10.1067/mcp.2002.126179

M3 - Article

C2 - 12152001

AN - SCOPUS:0036331674

VL - 72

SP - 20

EP - 32

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 1

ER -