Sanofi, R&D, TD Diabetes, Industriepark Hoechst, Frankfurt am Main, Germany.
Sanofi, R&D, Drug Metabolism and Pharmacokinetics, Industriepark Hoechst, Frankfurt am Main, Germany.
Diabetes Obes Metab. 2022 Dec;24(12):2411-2419. doi: 10.1111/dom.14827. Epub 2022 Aug 16.
To report the in vitro and in vivo preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties of RA15127343, a novel ultralong-acting insulin analogue targeting once-weekly administration, in female Göttingen minipigs.
In vitro binding and activation of human insulin receptor isoforms (IR-A/IR-B), glucose uptake in rat myocytes, as well as mitogenic activity of RA15127343 were evaluated. In vivo, the PK and PD activities of RA15127343 were assessed in female, normoglycaemic Göttingen minipigs. The half-life (t ) and time to maximum plasma concentration (T ) of subcutaneously (SC) administered RA15127343 (10/30/45/60 nmol/kg) were estimated. In vivo blood glucose and endogenous plasma C-peptide concentrations after single SC administration (10/30/45/60 nmol/kg) or repeated dosing (15 nmol/kg) were analysed.
In comparison to human insulin, RA15127343 showed lower in vitro binding affinity (19.9/6.31 μM vs. 1.10/1.14 nM) and activation (2.054 μM/669.6 nM vs. 26.04/18.24 nM) of IR-A/IR-B, lower potency to activate glucose uptake (855.2 vs. 3.37 nM) and lower mitogenic activity (17.92 μM vs. 10.78 nM; proliferation in MCF7 cells). In vivo, the mean t and T of RA15127343 after SC administration ranged from 48 to 59 and 30 to 39 hours, respectively. Blood glucose and plasma C-peptide concentrations were significantly lower with RA15127343 (single/repeated doses) versus vehicle.
RA15127343 showed an ultra-long t with a slow onset of action. The preclinical pharmacological outcomes suggest RA15127343 could be a potential ultralong-acting insulin analogue with low risk of hypoglycaemia in humans.
报告新型超长效胰岛素类似物 RA15127343 的体外和体内临床前药代动力学（PK）和药效学（PD）特性，该类似物针对每周一次给药。
评估 RA15127343 与人胰岛素受体同工型（IR-A/IR-B）的体外结合和激活、大鼠肌细胞中的葡萄糖摄取以及 RA15127343 的有丝分裂活性。在雌性正常血糖的哥廷根小型猪中，评估 RA15127343 的 PK 和 PD 活性。皮下（SC）给予 RA15127343（10/30/45/60nmol/kg）后，估算其半衰期（t）和达峰时间（T）。单次 SC 给药（10/30/45/60nmol/kg）或重复给药（15nmol/kg）后，分析体内血葡萄糖和内源性血浆 C 肽浓度。
与人胰岛素相比，RA15127343的体外结合亲和力（19.9/6.31μM 比 1.10/1.14nM）和激活（2.054μM/669.6nM 比 26.04/18.24nM）较低，激活葡萄糖摄取的效力较低（855.2 比 3.37nM），有丝分裂活性较低（17.92μM 比 10.78nM；MCF7 细胞增殖）。体内 SC 给药后，RA15127343 的平均 t 和 T 分别为 48 至 59 小时和 30 至 39 小时。与载体相比，RA15127343（单次/重复剂量）使血葡萄糖和血浆 C 肽浓度显著降低。
RA15127343具有超长的 t，作用缓慢。临床前药理学结果表明，RA15127343可能是一种具有潜在超长效作用的胰岛素类似物，在人体中低血糖风险较低。
