J. Chen, C. Dias, M. Bragasin, S. F. Wilson, N. Narayanan, G. Jang, P. Ma, T. Vu; Amgen Inc., Newbury Park, CA
BACKGROUND: AMG 747 is a highly selective small molecule GlyT-1 inhibitor. This analysis was to characterize AMG 747 PK and establish relationship between AMG 747 and glycine concentrations in cerebrospinal fluid (CSF) after oral administration of AMG 747 in healthy subjects.
METHODS: Plasma and CSF concentration time data were available from 38 healthy subjects receiving a single oral dose of placebo or AMG 747 at 7.5, 20, or 50 mg or a daily dose of AMG 747 at 20 mg for 14 days. Intensive plasma and CSF samples were collected over a 24 h period. AMG 747 and glycine concentrations were quantified using validated LC/MS/MS methods. Simultaneous population PKPD modeling was implemented to estimate AMG 747 parameters and their variability.
RESULTS: A three-compartment (CMT) model, sequential zero- and first-order absorption rates from the gut, first-order transfer rate from central to CSF CMT, and first-order elimination rates from central and CSF CMT best described the PK of AMG 747 in plasma and CSF. Oral absorption was rapid (ka = 5.53 h-1, %CV=107). Apparent clearance (CL/F) and volume of distribution at steady state ([V2+V3]/F) were ~ 0.645 L/h (%CV=19) and 28 L (%CV=16) for a 70 kg subject, respectively; terminal half-life was ~31 h; transfer rate from plasma to CSF was 2.34 mL/h (%CV=28); elimination rate from CSF was 37.8 mL/h (%CV=24). Body weight was a significant covariate on CL/F and V2/F. AMG 747 concentrations in CSF were linearly correlated to glycine concentrations for the dose range studied. For every 1ng/mL AMG 747 concentration increase in CSF, ~ 6% of glycine concentration increase from baseline (%CV = 56).
CONCLUSION: AMG 747 exhibits linear PK in both plasma and CSF, and significantly increases glycine concentrations in the CSF. This PKPD model was used in selecting doses for future dose ranging studies.