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Cited by 10Advanced Drug Delivery SystemsAlzheimer's disease research and treatmentsInhalation and Respiratory Drug Delivery

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

Lowe, Stephen, Sher, Emanuele, Wishart, Graham, Jackson, Kimberley, Yuen, Eunice, Brittain, Claire, Fong, Siew Chinn, Clarke, David O. +1 more·2017·Drug Delivery and Translational Research
DOI 10.1007/s13346-016-0325-8
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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 2) 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.

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  • Other studies have failed to detect increases in cerebrospinal fluid after intranasal insulin lispro delivery to healthy volunteers.

    “Considering that other studies have failed to detect increases in CSF after IN insulin delivery (albeit of the insulin analogue lispro) to healthy volunteers”

    From Intranasal insulin (2021) · cites this paper as [36]

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Authors
Lowe, S., Sher, E., Wishart, G., Jackson, K., Yuen, E., Brittain, C., Fong, S. C., Clarke, D. O., & Landschulz, W. H.
Affiliations
  • National University of Singapore (SG)
  • Eli Lilly (United Kingdom) (GB)
  • Eli Lilly (United States) (US)
Corresponding author
Lowe, Stephen
ORCID
Venue
Drug Delivery and Translational Research
Publisher
Springer Science and Business Media LLC
Published
2016-08-23
Volume
7
Issue
1
Pages
11-15
ISSN
  • 2190-393X (ISSN-L)
  • 2190-3948
DOI
10.1007/s13346-016-0325-8
OpenAlex
W2516916157
Cited by
10
References
8
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2021: 1 · 2019: 1 · 2018: 2 · 2017: 1
FWCI
0.76
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (unspecified)
Locations
  • Drug Delivery and Translational Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eli Lilly and Company
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
Keywords
insulin lispro, cerebrospinal fluid, Alzheimer's disease, pharmacokinetics, serum insulin, beagle dogs, healthy volunteers, exposure-response relationship, insulin analogues
MeSH terms
Administration, Intranasal, Animals, Dogs, Humans, Hypoglycemic Agents, Male, Middle Aged, Insulin Lispro, Healthy Volunteers

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