title: Alternative method of oral administration by peanut butter pellet formulation results in target engagement of BACE1 and attenuation of gavage-induced stress responses in mice.
abstract: Development of novel therapeutic agents aimed at treating neurodegenerative disorders such as Alzheimer's and Parkinson's diseases require chronic and preferentially oral dosing in appropriate preclinical rodent models. Since many of these disease models involve transgenic mice that are frequently aged and fragile, the commonly used oro-gastric gavage method of drug administration often confounds measured outcomes due to repeated stress and high attrition rates caused by esophageal complications. We employed a novel drug formulation in a peanut butter (PB) pellet readily consumed by mice and compared the stress response as measured by plasma corticosterone levels relative to oral administration via traditional gavage. Acute gavage produced significant elevations in plasma corticosterone comparable to those observed in mice subjected to stress-induced hyperthermia. In contrast, corticosterone levels following consumption of PB pellets were similar to levels in naive mice and significantly lower than in mice subjected to traditional gavage. Following sub-chronic administration, corticosterone levels remained significantly higher in mice subjected to gavage, relative to mice administered PB pellets or naive controls. Furthermore, chronic 30day dosing of a BACE inhibitor administered via PB pellets to PSAPP mice resulted in expected plasma drug exposure and Aβ40 lowering consistent with drug treatment demonstrating target engagement. Taken together, this alternative method of oral administration by drug formulated in PB pellets results in the expected pharmacokinetics and pharmacodynamics with attenuated stress levels, and is devoid of the detrimental effects of repetitive oral gavage.
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA; Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA. Electronic address: cathleen.gonzales@pfizer.com.
authors.forename: C
authors.initials: C
authors.lastname: Gonzales
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA; Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Zaleska
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA; Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Riddell
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA; Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Atchison
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: A
authors.initials: A
authors.lastname: Robshaw
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Neuroscience, Wyeth Research (currently Pfizer Inc.), Princeton, NJ, USA; Neuroscience Research Unit, Pfizer Inc., 448 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood; D000818:Animals; D010367:Arachis; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003345:Corticosterone / Q000097:blood; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005334:Fever / Q000097:blood; D007441:Intubation, Gastrointestinal / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D003345:Corticosterone
keywords: Aβ; BACE1; Chronic oral dosing method; Corticosterone; Mouse; Stress