药效学
生物利用度
化学
分配量
最大值
口服
分布(数学)
曲线下面积
半衰期
作者
Cynthia Sung,Tom J. Parry,Todd A. Riccobene,Angela Mahoney,Viktor Roschke,James H. Murray,Mi Li Gu,Jeffrey K. Glenn,Florence A. Caputo,Cindy Farman,Daniel Odenheimer
出处
期刊:Aaps Pharmsci
[American Association of Pharmaceutical Scientists]
日期:2002-01-01
卷期号:4 (2): 24-33
被引量:23
摘要
Repifermin (truncated, recombinant human keratinocyte growth factor-2, KGF-2) was evaluated in cynomolgus monkeys and healthy humans during a phase 1 trial. Monkeys received vehicle or repifermin at 20, 75, or 200 μg/kg IV or 750 μg/kg subcutaneous (SC) daily for 29 days. Clinical observations were made during the entire dosing period. Gross and microscopic changes were assessed at necropsy. Pharmacokinetic parameters and immunogenicity were evaluated in these monkeys and in humans, following a single or 7 daily IV bolus injections of 1, 5, 25, or 50 μg/kg repifermin. In monkeys, repifermin was well tolerated, and histologic evaluation demonstrated dose-dependent, reversible thickening of the mucosa throughout the alimentary tract, except for the stomach. In the alimentary tract tissues, nonepithelial tissues were not affected, indicating a specificity of repifermin for epithelial cells. Pharmacokinetics in both monkeys and humans were dose proportional, showed lack of drug accumulation with repeated daily dosing, and were characterized by high volumes of distribution and clearance rates, indicating substantial tissue binding and metabolism. Repifermin was not markedly immunogenic following multiple daily IV injections in either species. Serum repifermin concentrations in humans were comparable to those attained in monkeys that produced significant pharmacological effects on epithelial cells in the alimentary tract. These findings provide additional support for the ongoing clinical development of repifermin for diseases involving epithelial injury.
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