Pharmacokinetics and Pharmacodynamics of Recombinant FGF-2 in a Phase I Trial in Coronary Artery Disease

• Published in: Journal of clinical pharmacology Vol. 41; no. 4; pp. 378 - 385
• Main Authors: Bush, Mark A., Samara, Emil, Whitehouse, M. J., Yoshizawa, Carl, Novicki, Deborah L., Pike, Marilyn, Laham, Roger J., Simons, Michael, Chronos, Nicolas A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2001; SAGE Publications; Sage Science; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Area Under Curve; Biological and medical sciences; Cardiovascular system; Coronary Disease - drug therapy; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2 - administration & dosage; Fibroblast Growth Factor 2 - adverse effects; Fibroblast Growth Factor 2 - pharmacokinetics; Fibroblast Growth Factor 2 - pharmacology; Follow-Up Studies; Hemodynamics - drug effects; Heparin - pharmacology; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Medical sciences; Metabolic Clearance Rate; Middle Aged; Miscellaneous; Pharmacology. Drug treatments; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; Regression Analysis; Time Factors; Human; Fibroblast growth factor; Intravenous administration; Coronary artery; Cardiovascular disease; Coronary heart disease; Dose activity relation; Perfusion; Phase I trial; Intraarterial administration; Hemodynamics; Recombinant protein; Pharmacokinetics
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/00912700122010230

Fibroblast growth factor‐2 (FGF‐2) is a heparin‐binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF‐2 (rFGF‐2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF‐2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF‐2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration‐time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 μg/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF‐2 infusion, consistent with slower clearance of heparin/rFGF‐2 complexes. Infusion of rFGF‐2 was associated with changes in acute hemodynamics. While a clear PK/PD dose‐response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF‐2 doses was observed.