Byrd Richard A, Blackbourne Jamie L, Knadler Mary Pat, Schultze Albert E, Vahle John L
1 Non-Clinical Safety Assessment, Eli Lilly and Company, Indianapolis, Indiana, USA.
2 Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana, USA.
Toxicol Pathol. 2017 Apr;45(3):402-415. doi: 10.1177/0192623317696283. Epub 2017 Jan 1.
Basal insulin peglispro (BIL) consists of insulin lispro with a 20-kDa polyethylene glycol (PEG) moiety covalently attached to lysine B28. Because chronic parenteral administration of PEGylated proteins to animals has sometimes resulted in PEG vacuolation of tissue macrophages, renal tubular cells, and choroid plexus ependymal cells, we investigated whether chronic subcutaneous (sc) injection of BIL in rats (52 weeks) and dogs (39 weeks) was associated with systemic toxicities or other changes, including vacuolation of tissue macrophages, renal tubular cells, and ependymal cells. Rats and dogs received daily sc injections of BIL (rats: 0.17, 0.45, or 1.15 mg/kg/d and dogs: 0.025, 0.10, or 0.20 mg/kg/d) and the reference compound, HUMULIN N® (neutral protamine Hagedorn [NPH] human insulin; rats: 0.15 mg/kg/d and dogs: 0.02-0.03 mg/kg/d). Animals were evaluated for standard end points including mortality, clinical signs, body weights, toxicokinetics, glucodynamics, clinical pathology, and morphological pathology. Nonadverse injection site lipohypertrophy occurred for all BIL and NPH doses but more frequently with BIL. No BIL-related hyperplasia or neoplasia was observed. There was no vacuolation of tissue macrophages, renal tubular cells, or ependymal cells attributable to PEG. These studies demonstrate BIL is not associated with tissue vacuolation attributable to PEG at 4- to 6-fold multiple of the median clinical exposure in patients with diabetes.
聚乙二醇化赖脯胰岛素（BIL）由赖氨酸B28共价连接20 kDa聚乙二醇（PEG）部分的赖脯胰岛素组成。由于对动物长期肠胃外给予聚乙二醇化蛋白有时会导致组织巨噬细胞、肾小管细胞和脉络丛室管膜细胞出现PEG空泡化，我们研究了在大鼠（52周）和犬（39周）中长期皮下注射BIL是否会导致全身毒性或其他变化，包括组织巨噬细胞、肾小管细胞和室管膜细胞的空泡化。大鼠和犬每日皮下注射BIL（大鼠：0.17、0.45或1.15 mg/kg/天；犬：0.025、0.10或0.20 mg/kg/天）以及参比化合物优泌林N®（中性鱼精蛋白锌[NPH]人胰岛素；大鼠：0.15 mg/kg/天；犬：0.02 - 0.03 mg/kg/天）。对动物进行标准终点评估，包括死亡率、临床体征、体重、毒代动力学、糖动力学、临床病理学和形态病理学。所有BIL和NPH剂量均出现非不良注射部位脂肪增生，但BIL更常见。未观察到与BIL相关的增生或肿瘤形成。未发现可归因于PEG的组织巨噬细胞、肾小管细胞或室管膜细胞空泡化。这些研究表明，在糖尿病患者临床中位暴露量的4至6倍时，BIL与可归因于PEG的组织空泡化无关。
