Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.
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 micrograms/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.
Bush
M A
MA
Chiron Corporation, 4560 Horton Street M/S 4. 178, Emeryville, CA 94608-2916, USA.
Samara
E
E
Whitehouse
M J
MJ
Yoshizawa
C
C
Novicki
D L
DL
Pike
M
M
Laham
R J
RJ
Simons
M
M
Chronos
N A
NA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003327:Coronary Disease / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D012044:Regression Analysis; D013997:Time Factors
D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D006493:Heparin