Kletzl H, Guenther A, Höflich A, Höflich C, Frystyk J, Staack R F, Schick E, Wandel C, Bleich N, Metzger F
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Department of Signal Transduction, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
Growth Horm IGF Res. 2017 Apr;33:9-16. doi: 10.1016/j.ghir.2017.01.001. Epub 2017 Jan 10.
This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I.
The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated.
PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV.
PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.
本研究首次评估RO5046013在人体中的安全性、耐受性、药代动力学和药效学，并与未修饰的重组人胰岛素样生长因子I（rhIGF-I）进行比较。
该研究在法国的一个临床研究单位进行，为单中心、随机、双盲、安慰剂对照、单剂量递增、平行组研究。共有62名健康志愿者参与了这项临床试验。RO5046013以单次皮下注射或在48小时内静脉输注的方式给药，剂量逐步递增。活性对照rhIGF-I以50μg/kg皮下注射，每日两次，共4天。对RO5046013的安全性、耐受性、药代动力学和药效学进行了评估。
聚乙二醇化导致RO5046013的暴露时间延长，半衰期为140 - 200小时。RO5046013的暴露量大致呈剂量比例增加。RO5046013在所有剂量下均安全且耐受性良好，皮下给药后注射部位红斑是最常观察到的不良事件。未发生低血糖。给予rhIGF-I后生长激素（GH）分泌几乎完全被抑制，而RO5046013在静脉给予最高剂量时仅导致GH适度下降。
IGF-I的聚乙二醇化显著延长半衰期，降低GH负反馈和低血糖风险，因此在相关疾病治疗中为rhIGF-I提供了有价值的替代方案。
