Lowe Stephen, Sher Emanuele, Wishart Graham, Jackson Kimberley, Yuen Eunice, Brittain Claire, Fong Siew Chinn, Clarke David O, Landschulz William H
Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD11), National University of Singapore, 10 Medical Drive, Singapore, 117597, Singapore.
Eli Lilly and Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, England.
Drug Deliv Transl Res. 2017 Feb;7(1):11-15. doi: 10.1007/s13346-016-0325-8.
Intranasally administered regular insulin and insulin aspart have shown cognitive benefit for patients with Alzheimer's disease (AD). To support development of intranasally administered insulin analogs for AD, the central disposition of intranasal insulin lispro in the cerebrospinal fluid (CSF) of healthy volunteers was investigated. Healthy volunteers (N = 8) received two sequential doses of intranasal insulin lispro (48 or 80 IU followed by 160 IU) by Aero Pump in an open-label, single-period study with serial CSF and serum sampling over 5 hours after each dose. CSF insulin lispro was also measured in beagle dogs (N = 6/dose group) that received either 24 IU/kg (equivalent local nasal (IU/cm) dose to the human 160 IU dose) or 192 IU/kg intranasally, using the same device. Insulin lispro was measured in the CSF and serum using a validated enzyme-linked immunosorbent assay method, and pharmacokinetic parameters were calculated by standard noncompartmental methods. Intranasal administration of insulin lispro was well tolerated. Insulin lispro concentrations in the CSF of humans at all dose levels were below the limit of quantification. Serum insulin lispro concentrations were quantifiable only up to 1-2 hours in the majority of subjects. In contrast to insulin lispro in the CSF of humans, insulin lispro was detectable in the CSF at both dose levels in dogs, and serum concentrations of insulin lispro were generally higher in dogs than in healthy volunteers. The absence of insulin lispro in CSF from healthy volunteers and the lack of robust exposure-response analyses will hinder the development of intranasally administered insulin lispro for AD.
经鼻给予常规胰岛素和门冬胰岛素已显示出对阿尔茨海默病（AD）患者的认知益处。为支持经鼻给予胰岛素类似物用于AD的研发，对健康志愿者脑脊液（CSF）中鼻内给予赖脯胰岛素的中枢分布进行了研究。在一项开放标签、单周期研究中，8名健康志愿者通过空气泵依次接受两剂鼻内赖脯胰岛素（48或80 IU，随后为160 IU），每次给药后5小时进行连续的CSF和血清采样。还使用相同装置对每组6只比格犬经鼻给予24 IU/kg（相当于人类160 IU剂量的局部鼻内（IU/cm）剂量）或192 IU/kg的赖脯胰岛素后进行CSF中赖脯胰岛素的测量。使用经过验证的酶联免疫吸附测定法测量CSF和血清中的赖脯胰岛素，并通过标准的非房室方法计算药代动力学参数。鼻内给予赖脯胰岛素耐受性良好。所有剂量水平的人类CSF中赖脯胰岛素浓度均低于定量限。在大多数受试者中，血清赖脯胰岛素浓度仅在1 - 2小时内可定量。与人类CSF中的赖脯胰岛素不同，在两个剂量水平的犬CSF中均检测到赖脯胰岛素，且犬的血清赖脯胰岛素浓度通常高于健康志愿者。健康志愿者CSF中缺乏赖脯胰岛素以及缺乏有力的暴露 - 反应分析将阻碍鼻内给予赖脯胰岛素用于AD的研发。
