title: Semagacestat pharmacokinetics are not significantly affected by formulation, food, or time of dosing in healthy participants.
abstract: Semagacestat, a γ-secretase inhibitor, reduces formation of amyloid beta peptide. Two single-dose (140 mg), open-label, randomized, 3-period, crossover studies evaluated the effect of formulation, food, and time of dosing on the pharmacokinetics and pharmacodynamics of semagacestat in healthy participants. The first study (n = 14) compared tablet to capsules. For all formulations, the median time to maximum plasma concentration (t(max)) was generally 1.0 hour. Plasma elimination was rapid, with a half-life of approximately 2.5 hours. Tablet form II bioavailability (F) relative to capsule was approximately 100% (F = 1.03 [90% confidence interval (CI), 0.96-1.10]). In the second study, participants (n = 27) received semagacestat either fed or fasting in the morning or fasting in the evening. No significant change in exposure (AUC(0-∞) [area under the concentration-time curve from 0 to infinity] ratio = 1.02, [90% CI, 0.990-1.05]) occurred with food, whereas maximum plasma concentration (C(max)) declined approximately 15%, and median t(max) was delayed to 1.5 hours. Time of dosing made no significant difference in AUC(0-∞), C(max), or t(max) (AUC(0-∞) ratio 1.01, [90% CI, 0.975-1.04]). No clinically significant safety concerns occurred in either study. Accordingly, semagacestat may be dosed without regard to formulation, food, or time of administration.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. willisba@lilly.com
authors: Brian A
authors: BA
authors: Willis
authors: Wei
authors: W
authors: Zhang
authors: Mosun
authors: M
authors: Ayan-Oshodi
authors: Stephen L
authors: SL
authors: Lowe
authors: William F
authors: WF
authors: Annes
authors: Paul J
authors: PJ
authors: Sirois
authors: Stuart
authors: S
authors: Friedrich
authors: Amparo
authors: A
authors: de la Peña
mesh_terms: D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood; D001381:Azepines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D010352:Patient Dropouts; D010446:Peptide Fragments / Q000097:blood; D013607:Tablets
chemical_list: D016229:Amyloid beta-Peptides; D001381:Azepines; D002214:Capsules; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D018697:Nootropic Agents; D010446:Peptide Fragments; D013607:Tablets; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D000409:Alanine