An assessment of the central disposition of intranasally administered insulin lispro in the cerebrospinal fluid of healthy volunteers and beagle dogs

Abstract

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.

Intranasal insulin

“…34 Experiments in healthy humans have shown that IN administered insulin bypasses the BBB and is detectable in CSF within 1 hour after administration. 35 Considering that other studies have failed to detect increases in CSF after IN insulin delivery (albeit of the insulin analogue lispro) to healthy volunteers, 36 further straightforward evidence for the central bioavailability of IN insulin (also in clinical cohorts such as patients with type 2 diabetes or AD) would be welcome evidence for the effectiveness of IN insulin delivery. The currently available devices for IN delivery range from simple nasal atomisers, 37 which have been proven to reliably trigger functional effects in healthy humans, [38][39][40][41][42][43][44][45][46][47] to more sophisticated appliances, which, for example, use a liquid hydrofluoroalkane propellant to eject a metered dose of insulin to target the upper third of the nasal cavity and thereby optimally reach the olfactory epithelium.…”

Insulin Delivery to the Brain via the Nasal Route: Unraveling the Potential for Alzheimer's Disease Therapy

“…These findings suggested that intranasal treatment may benefit populations with certain demographic backgrounds more than others. The variation in therapeutic outcomes could also be attributed to the difference in anatomy (e.g., distance from the nasal cavity to the brain), ethnicity, brain size and metabolic differences [ 102 , 109 ]. Hence, a comprehensive understanding of the patient’s features, such as clinical background, can assist in the establishment of personalised therapeutic regimens and more accurate prediction of treatment outcomes.…”

“…Multiple studies have described the effective disposition of regular insulin and rapid-acting insulin (e.g., insulin aspart) in the CNS [ 109 ]. Lowe et al performed an analysis on the central localization of intranasally administered insulin lispro in the cerebrospinal fluid of healthy participants [ 109 ]. In the study, two daily doses of insulin (i.e., 48 or 80 IU in the morning and 160 IU in the afternoon) were administered using an Aero Pump.…”

“…In the study, two daily doses of insulin (i.e., 48 or 80 IU in the morning and 160 IU in the afternoon) were administered using an Aero Pump. It was reported that insulin lispro successfully reached the blood circulation 30–120 min after dosing, but not detectable in cerebrospinal fluid [ 109 ]. The reason for the discrepancy in the effects of insulin lispro and regular insulin could be attributed to the small sample size, short treatment period, and demographic characteristics amongst different trials.…”

Pharmacokinetics and Tissue Distribution Kinetics of Puerarin in Rats Using Indirect Competitive ELISA

“…This method offers advantages in pharmacokinetic study, including simple sample preparation requiring only phosphate-buffered saline (PBS), water, or other solvents for dilution [17], high sensitivity to detect trace amounts of sample [18], high specificity, easy operation, and high-throughput capability to detect a large number of samples simultaneously [19,20]. …”