Sinha Vikram P, Choi Siak Leng, Soon Danny Kwang Wei, Mace Kenneth F, Yeo Kwee Poo, Lim Shufen T H, Howey Daniel C
Eli Lilly and Company, Indianapolis, IN, USA.
J Clin Pharmacol. 2014 Jul;54(7):792-9. doi: 10.1002/jcph.276. Epub 2014 Feb 13.
LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.
LY2605541是一种作用持续时间延长的新型基础胰岛素类似物。两项I期研究评估了LY2605541在健康受试者中的药代动力学（PK）、糖动力学（GD）和耐受性。在研究1中，33名受试者接受了单次皮下（SC）注射LY2605541（0.01 - 2.22 U/kg）和甘精胰岛素（0.5 - 0.8 U/kg），随后进行持续24 - 36小时的正常血糖钳夹试验。在研究2中，通过比较皮下注射与静脉注射的剂量标准化浓度-时间曲线下面积，评估了8名受试者皮下注射LY2605541的绝对生物利用度。皮下注射LY2605541的达峰时间（中位数）以及半衰期（t½）和表观清除率的几何均值分别为18.0至42.0小时、24.4 - 45.5小时和1.8 - 2.8 L/h，而皮下注射甘精胰岛素的相应值为10.0 - 12.0小时、12.2 - 14.9小时和51.4 - 65.2 L/h。与甘精胰岛素的葡萄糖输注速率（GIR）曲线在24小时时下降不同，LY2605541的GIR曲线持续≥36小时。静脉注射后，LY2605541的几何均值t½为2.3小时。LY2605541的PK参数受试者内变异（CV%）<18%，GD参数<32%。最常见的不良事件与研究操作有关，严重程度为轻至中度。这些结果确定了LY2605541耐受性良好的基线剂量，其PK曲线相对平稳，受试者内变异较低。
