Abstracts

RATIONALE: Retigabine is a novel antiepileptic compound with the potential to be effective in refractory patients. Retigabine is mainly eliminated as N-acetyl and N-glucuronide metabolites. Retigabine does not induce or inhibit its own metabolism. The constituants of a steroidal oral contraceptive are extensively metabolised by liver enzymes including the cytochrome P450 3A4 and conjugating enzymes. When administering a new compound to women taking steroidal oral contraceptives, it is important to know if they will still be exposed to efficacious concentrations of contraceptives. The objecive was to evaluate the potential effect of retigabine, a new antiepileptic drug, on the pharmacokinetics (PK) of a low dose oral contraceptive (ethinyl estradiol / norgestrel).
METHODS: Lo-Ovral (ethinyl estradiol 0.03 mg / norgestrel 0.3 mg) was administered to 18 women (range of 18 to 42 years) for two menstrual cycles. Retigabine (150 mg TID) was administered from Days 10 to 13 to achieve steady-state of the second cycle. Pharmacokinetic profiles for ethinyl estradiol and norgestrel were obtained on Day 13 of both cycles. Trough concentrations of retigabine were obtained on Days 12, 13 and 14. Drug levels were determined by validated methods. Pharmacokinetic parameters were obtained by noncompartmental methods and compared statistically using analyses of variance and confidence intervals. Safety was monitored during the study.
RESULTS: When Lo-Ovral was administered alone, the pharmacokinetics of ethinyl estradiol were characterized by a mean [plusminus] SD AUC of 881 [plusminus] 281 pg.h/mL and a Cmax of 79.3 [plusminus] 25.6 pg/mL and the pharmacokinetics of norgestrel were characterized by an AUC of 100 [plusminus] 36 ng.h/mL and a mean Cmax of 7.69 [plusminus] 2.5 ng/mL. After administration of Lo-Ovral with retigabine the pharmacokinetic parameters for both ethinyl estradiol and norgestrel did not change significantly as the geometric mean parameter ratios were between 94% and 100%. Preliminary review of safety through monitoring reports indicate no clinically important changes in laboratory values, vital signs or ECGs. Common adverse events were mild and included headaches, nausea, increased sleepiness and vaginitis. No serious adverse events were reported and no one discontinued due to an adverse event. Retigabine administration was overall well tolerated.
CONCLUSIONS: Retigabine did not alter the pharmacokinetics of ethinyl estradiol and norgestrel. These data suggest that women on oral contraceptives can take retigabine without the need for backup contraception.
Support: Wyeth Ayerst Research.
Disclosure: Salary - Authors are full-time employees of Wyeth Ayerst.; Grant - NA; Equity - NA; Consulting - NA; Ownership - NA; Materials - NA; Stock - NA; Royalties - NA; Honoraria - NA; Other - NA