Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady‐state in healthy subjects

British Journal of Clinical Pharmacology - Tập 56 Số 1 - Trang 39-45 - 2003
Géraldine M. Ferron1, Alain Patat2, Virginia Parks2, Paul Rolan3, Steven Troy1
1Clinical Pharmacology Department, Wyeth Research, Collegeville, PA, USA,
2Clinical Pharmacology Department, Wyeth Research, Paris, France and
3Medeval, Manchester, UK

Tóm tắt

Aims  To evaluate potential pharmacokinetic interactions between phenobarbitone and retigabine, a new antiepileptic drug. Methods  Fifteen healthy men received 200 mg of retigabine on day 1. On days 4–32, phenobarbitone 90 mg was administered at 22.00 h. On days 26–32, increasing doses of retigabine were given to achieve a final dose of 200 mg every 8 h on day 32. The pharmacokinetics of retigabine were determined on days 1 and 32, and those for phenobarbitone on days 25 and 31.Results  After administration of a single 200 mg dose, retigabine was rapidly absorbed and eliminated with a mean terminal half‐life of 6.7 h, a mean AUC of 3936 ng ml−1 h and a mean apparent clearance of 0.76 l h−1 kg−1. Similar exposure to the partially active acetylated metabolite (AWD21‐360) of retigabine was observed. After administration of phenobarbitone dosed to steady‐state, the pharmacokinetics of retigabine at steady‐state were similar (AUC of 4433 ng ml−1 h and t1/2 of 8.5 h) to those of retigabine alone. The AUC of phenobarbitone was 298 mg l−1 h when administered alone and 311 mg ml−1 h after retigabine administration. The geometric mean ratios and 90% confidence intervals of the AUC were 1.11 (0.97, 1.28) for retigabine, 1.01 (0.88, 1.06) for AWD21‐360 and 1.04 (0.96, 1.11) for phenobarbitone. Individual and combined treatments were generally well tolerated. One subject was withdrawn from the study on day 10 due to severe abdominal pain. Headache was the most commonly reported adverse event. No clinically relevant changes were observed in the electrocardiograms, vital signs or laboratory measurements.Conclusions  There was no pharmacokinetic interaction between retigabine and phenobarbitone in healthy subjects. No dosage adjustment is likely to be necessary when retigabine and phenobarbitone are coadministered to patients.

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Tài liệu tham khảo

Rundfeldt CNR., 2000, Investigations into the mechanism of action of the new anticonvulsant retigabine, Arzneimittel Forsch Drug Res, 50, 1063

10.1124/mol.58.3.591

10.1523/JNEUROSCI.21-15-05535.2001

10.1016/0920-1211(95)00101-8

10.1111/j.1528-1157.2000.tb01501.x

10.1016/S0920-1211(99)00065-0

10.1016/S0920-1211(01)00193-0

10.1007/s002100000361

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

10.1177/00912700222011210

Levy R, 1992, Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring

10.1016/0009-9236(95)90244-9

10.2165/00003088-199631030-00004

10.1016/S0920-1211(00)00160-1

10.1016/S0378-4347(00)00272-3

Rowland M, 1989, Clinical pharmacokinetics: concepts and applications

10.1007/BF01068419

10.1111/j.1528-1157.2000.tb02944.x

10.1111/j.1472-8206.2000.tb00411.x

10.2165/00003088-199631060-00005

10.2165/00003088-199631040-00006

10.1592/phco.20.12.139S.35255

Ferron GM, 2001, Pharmacokinetic interaction between valproic acid, topiramate, phenytoin or carbamazepine and retigabine in epileptic patients, Clin Pharmacol Ther, 69, 18

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Thông tin xuất bản

British Journal of Clinical Pharmacology

Tập 56 Số 1

39-45

Thông tin tác giả