Semagacestat pharmacokinetics are not significantly affected by formulation, food, or time of dosing in healthy participants

• Published in: Journal of clinical pharmacology Vol. 52; no. 6; p. 904
• Main Authors: Willis, Brian A, Zhang, Wei, Ayan-Oshodi, Mosun, Lowe, Stephen L, Annes, William F, Sirois, Paul J, Friedrich, Stuart, de la Peña, Amparo
• Format: Journal Article
• Language: English
• Published: England 01.06.2012
• Subjects: Aged; Alanine - administration & dosage; Alanine - analogs & derivatives; Alanine - blood; Alanine - pharmacokinetics; Alanine - pharmacology; Amyloid beta-Peptides - blood; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Azepines - administration & dosage; Azepines - blood; Azepines - pharmacokinetics; Azepines - pharmacology; Biological Availability; Capsules; Chemistry, Pharmaceutical; Cross-Over Studies; Drug Administration Schedule; Female; Food-Drug Interactions; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Nootropic Agents - administration & dosage; Nootropic Agents - blood; Nootropic Agents - pharmacokinetics; Nootropic Agents - pharmacology; Patient Dropouts; Peptide Fragments - blood; Tablets
• ISSN: 1552-4604
• DOI: 10.1177/0091270011407195

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.