Abstracts

Rationale: To assess the effects of therapeutic dosages of retigabine (RTG) on steady-state pharmacokinetics of a combination oral contraceptive (OC) containing 1 mg norethindrone and 0.035 mg ethinyl estradiol. Methods: This was an open-label drug interaction study in 30 healthy women, 18-55 yrs of age, BMI 18-28 kg/m², with regular menstrual cycles. Subjects received an active OC tablet once daily during Period 1 (Days 1-21) and Period 3 (Days 29-49) and a placebo OC tablet once daily during Period 2 (Days 22-28). RTG dosing as a TID regimen was initiated on Day 22 at 300 mg/day, with dose escalations on the following days: Day 25, 450 mg/day; Day 28, 600 mg/day; Day 31, 750 mg/day and Day 34, 900 mg/day. Due to subject tolerability, RTG was reduced to 750 mg/day on Day 35 for the study duration. Serial blood samples were collected on Days 21 and 49 for determination of OC steady-state pharmacokinetics prior to and during RTG administration, respectively, and on Days 28 and 49 for determination of RTG steady-state pharmacokinetics during placebo and active OC dosing, respectively. Pharmacokinetic parameters were determined using non-compartmental methods and potential interactions were assessed using a confidence interval approach. Results: 25 of 30 subjects completed the study. Neither norethindrone nor ethinyl estradiol exposure was reduced with RTG coadministration, indicating that repeated RTG dosing did not induce OC hormone metabolism. An observed 28% increase in norethindrone exposure (AUC) and 21% decrease in ethinyl estradiol Cmax are not expected to impact the clinical activity of the OC hormones. Dose-normalized RTG Cmax and AUC were unchanged with concomitant OC coadministration relative to the placebo OC period. Most adverse events (AEs) occurred after RTG was introduced with rapid titration. The most common AEs were gastrointestinal and CNS effects. Most AEs were mild in severity although moderate or severe AEs were associated with the increase to RTG 900 mg/day, prompting a reduction to RTG 750 mg/day for better tolerability during the remainder of the study. No medically important trends were observed in clinical laboratory, vital sign, or ECG findings during the study. Overall, the regimen of RTG rapidly titrated to 900 mg/day was not well tolerated by the healthy female subjects in this study. Conclusions: Repeated RTG administration at therapeutic dosages does not reduce overall OC hormone exposure. These results suggest no potential for reduced OC efficacy due to RTG induction of OC hormone metabolism. In addition, there was no evidence of a direct effect of OCs on RTG pharmacokinetics. Funded by Valeant Pharmaceuticals International.