Multiple‐Dose, Linear, Dose‐Proportional Pharmacokinetics of Retigabine in Healthy Volunteers

Journal of Clinical Pharmacology - Tập 42 Số 2 - Trang 175-182 - 2002
Géraldine M. Ferron1, Jeffrey Paul1, Richard J. Fruncillo1, Lyette S Richards1, Norbert Knebel2, John Getsy1, Steven Troy1
1Wyeth‐Ayerst Research, Philadelphia, Pennsylvania.
2ASTA Medica, Frankfurt, Germany

Tóm tắt

Retigabine, a first‐in‐class selective M‐current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo‐controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half‐life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmacokinetics was linearly dose proportional. Steady‐state pharmacokinetics was in agreement with single‐dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21‐360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed‐dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.

Từ khóa


Tài liệu tham khảo

Sandercock PAG, 1996, Medicine.

10.1056/NEJM199606133342407

10.1016/S0140-6736(00)02515-0

10.1517/13543784.8.10.1497

10.1111/j.1527-3458.1996.tb00304.x

10.1124/mol.58.2.253

10.1124/mol.58.3.591

10.1038/sj.bjp.0703861

Hirsch E, Benign neonatal familial convulsions: a model of idiopathic epilepsy, Rev Neurol (Paris), 199, 463

10.1016/0014-2999(96)00073-8

10.1016/0920-1211(95)00101-8

Hempel R, 1999, Metabolism of retigabine (D‐23129), a novel anticonvulsant, Drug Metab Disp, 27, 613

10.1080/004982597240424

10.1016/S0920-1211(98)00108-9

10.1016/S0378-4347(00)00272-3

Rowland M, 1989, Clinical Pharmacokinetics: Concepts and Applications.

10.1177/00912709922007949

Thông tin
Thông tin xuất bản

Journal of Clinical Pharmacology

Tập 42 Số 2

175-182

Thông tin tác giả