caa a22 4500 475818105 CHVBK 20180406123814.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1007/s002280050709 doi (NATIONALLICENCE)springer-10.1007/s002280050709 Pharmacokinetics of a glycine site antagonist (gavestinel) following multiple dosing in patients with acute stroke [Elektronische Daten] [J. F. Hoke, A. G. Dyker, R. J. Barnaby, K. R. Lees] 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 · 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. Springer-Verlag Berlin Heidelberg, 2000 Key words Gavestinel nationallicence Pharmacokinetics nationallicence Acute stroke nationallicence Hoke J. F. Clinical Pharmacology, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA e-mail: jfh12180@glaxowellcome.com Tel.: +1-919-4838238; Fax: +1-919-4836380, US aut Dyker A. G. Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, GB aut Barnaby R. J. Drug Metabolism, Glaxo Wellcome SpA, Verona, Italy, IT aut Lees K. R. Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, GB aut https://doi.org/10.1007/s002280050709 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050709 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hoke J. F. Clinical Pharmacology, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA e-mail: jfh12180@glaxowellcome.com Tel.: +1-919-4838238; Fax: +1-919-4836380, US aut NATIONALLICENCE 700 1- Dyker A. G. Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, GB aut NATIONALLICENCE 700 1- Barnaby R. J. Drug Metabolism, Glaxo Wellcome SpA, Verona, Italy, IT aut NATIONALLICENCE 700 1- Lees K. R. Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, GB aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer