Pharmacokinetics of a glycine site antagonist (gavestinel) following multiple dosing in patients with acute stroke

Objective: The objective of this study was to characterize the pharmacokine tics of gavestinel in patients with acute stroke. Methods: Gavestinel was administered as an 800-mg loading dose and followed by either 100-, 200-, or 400-mg maintenance doses given every 12 h for fiv e doses. Blood and urine samples were collected for pharmacokinetic evaluat ion. The pharmacokinetics of gavestinel were determined using compartmental analysis. Results: The mean clearance (CL) and central (Vc) and steady-state (Vss) vo lumes of distribution across the dose groups were 0.31-0.40 l.h(-1), 3.3-3. 91, and 9.8-17 l, respectively. The mean terminal half-life ranged from 29 h to 56 h. Gavestinel was extensively bound to plasma protein (median perce ntage free <0.01). During gavestinel administration, some patients exhibite d elevated levels of bilirubin, which may be the result of shared mechanism s of elimination (glucuronide conjugation and excretion in bile). Conclusions: This study characterized the pharmacokinetics of gavestinel fo llowing multiple doses in acute stroke patients and showed that the pharmac okinetics are similar for increasing maintenance doses. The high protein bi nding of gavestinel was confirmed in acute stroke patients. A pharmacokinet ic interaction between gavestinel and bilirubin may contribute to the incre ase in bilirubin.