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 pharmacokinetics 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 five doses. Blood and urine samples were collected for pharmacokinetic evaluation. The pharmacokinetics of gavestinel were determined using compartmental analysis.


RESULTS
The mean clearance (CL) and central (Vc) and steady-state (Vss) volumes of distribution across the dose groups were 0.31-0.40 l x h(-1), 3.3-3.9 l, 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 percentage free <0.01). During gavestinel administration, some patients exhibited elevated levels of bilirubin, which may be the result of shared mechanisms of elimination (glucuronide conjugation and excretion in bile).


CONCLUSIONS
This study characterized the pharmacokinetics of gavestinel following multiple doses in acute stroke patients and showed that the pharmacokinetics are similar for increasing maintenance doses. The high protein binding of gavestinel was confirmed in acute stroke patients. A pharmacokinetic interaction between gavestinel and bilirubin may contribute to the increase in bilirubin.
Hoke
J F
JF
Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, NC 27709, USA. jfh12180@glaxowellcome.com
Dyker
A G
AG
Barnaby
R J
RJ
Lees
K R
KR
D000368:Aged; D000369:Aged, 80 and over; D001663:Bilirubin / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018684:Glycine Agents / Q000493:pharmacokinetics*; D006801:Humans; D007211:Indoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011485:Protein Binding; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*
C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D001798:Blood Proteins; D018684:Glycine Agents; D007211:Indoles; D001663:Bilirubin