Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans

Semagacestat, a functional gamma-secretase inhibitor, has demonstrated the ability to reduce amyloid-beta formation both in vitro and in vivo. This study aimed to characterize the pharmacokinetics and disposition of semagacestat in humans. Six healthy male subjects received a single 140-mg oral dose of [(14)C]semagacestat as a solution. Semagacestat was rapidly absorbed, reaching peak plasma concentration (Tₘₐₓ) at approximately 0.5 hours, and was quickly eliminated from systemic circulation, with a terminal half-life (t₁/₂) of approximately 2.4 hours.

The primary circulating metabolites identified were M2 (resulting from hydrolysis of the amide bond near the benzazepine ring) and M3 (produced by benzylic hydroxylation of the benzazepine ring), accounting for approximately 27% and 10% of the total radioactivity exposure, respectively, based on the plasma concentration-time curve from 0 to 24 hours. Nearly LY450139 complete recovery of the radioactive dose was achieved within seven days post-dose, with 87% excreted in urine and 8% in feces. Approximately 44% of the administered dose was recovered as unchanged [(14)C]semagacestat in urine, indicating that renal excretion plays a significant role in its elimination. Metabolites M2 and M3, along with their secondary metabolites, each contributed to about 20% of the total dose recovered in excreta.

In vitro studies suggest that the formation of M3 is primarily mediated by CYP3A enzymes, with CYP3A5 being approximately twice as efficient as CYP3A4 in producing M3. Consequently, the relative levels of CYP3A4 and CYP3A5 in individuals are expected to influence the clearance of M3 following semagacestat exposure.