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

Abstract

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 x ml(-1) x h and a mean apparent clearance of 0.76 l x h(-1) x 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 x ml(-1) x h and t1/2 of 8.5 h) to those of retigabine alone. The AUC of phenobarbitone was 298 mg x l(-1) x h when administered alone and 311 mg x ml(-1) x 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 One subject was withdrawn from the study on day 10 due to severe abdominal pain.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.

Figure 1

Mean (± SE) concentration-time profiles of retigabine after administration of drug alone or with phenobarbitone in healthy male subjects. Retigabine 200-mg single dose (○); and retigabine 200-mg q8h with 90-mg daily phenobarbital (•).

Figure 2

Mean (± SE) concentration-time profiles of AWD21-360 after administration of retigabine alone or with phenobarbitone in healthy male subjects. Retigabine 200-mg single dose (○); and retigabine 200-mg q8h with 90-mg daily phenobarbital (•).

Figure 3

Mean (± SE) concentration-time profiles of phenobarbitone after administration of drug alone or with retigabine in healthy male subjects. Phenobarbital 90-mg daily (○); and phenobarbital 90-mg daily with retigabine 200-mg q8h (•).