Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease
Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease
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DOI：
10.1177/00912700122010230
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发表时间：
2001-04-01
影响因子：
2.9
通讯作者：
Chronos, NA
中科院分区：
文献类型：
--
作者：
Bush, MA;Samara, E;Chronos, NA
成纤维细胞生长因子-2（FGF-2）是一种肝素结合蛋白，能够在多种慢性缺血动物模型中诱导血管生成。在一项I期临床试验中，对66例严重冠心病患者进行了单次冠状动脉内或静脉输注重组FGF-2（rFGF-2）的药代动力学和药效学评价。rFGF-2显示双相消除，平均研究范围分布t（1/2）为21分钟，平均表观终末消除t（1/2）为7.6小时。冠脉内或静脉内给药后，rFGF-2的全身暴露量相当。血浆峰浓度和浓度-时间曲线下面积随剂量成比例增加，表明在检查的剂量范围（0.33 - 48.0 μ g/kg）内呈线性药代动力学。当肝素给药接近rFGF-2输注时，观察到更大的全身暴露，与肝素/rFGF-2复合物的清除较慢一致。输注rFGF-2与急性血流动力学变化相关。虽然未建立明确的PK/PD剂量-反应关系，但观察到rFGF-2剂量越高，低血压和心动过速的趋势越明显。(C)2001年，美国临床药理学学会。
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 t(1/2) of 21 minutes and a mean apparent terminal elimination t(1/2) 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 mug/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. (C) 2001 the American College of Clinical Pharmacology.