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 ph armacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 ( rFGF-2) administered by intracoronary or intravenous infusion were evaluate d in a Phase I trial in 66 patients with severe coronary artery disease. rF GF-2 displayed biphasic elimination with a mean studywide distribution t(1/ 2) of 21 minutes and a mean apparent terminal elimination t(1/2) of 7.6 hou rs. Systemic exposure to rFGF-2 was comparable following intracoronary or i ntravenous administration. Peak plasma concentration and area under the con centration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 mug/kg). Great er systemic exposure was observed when heparin was administered closer to r FGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexe s. Infusion of rFGF-2 was associated with changes in acute hemodynamics. Wh ile a clear PK/PD dose-response relationship was not established, a trend t oward hypotension and tachycardia with higher rFGF-2 doses was observed. (C ) 2001 the American College of Clinical Pharmacology.