Abstracts

RATIONALE: Topiramate (TPM) may be preferentially used in women because of its clinical profile, including effectiveness in disorders that are more common in females (eg, JME; migraine) and low risk of weight gain. In an early interaction study with TPM and oral contraceptives (OCs) in women with epilepsy, TPM added to valproate was associated with no effect on the progestin (norethindrone, NE) pharmacokinetics and a modest dose-related decrease in estrogen (ethinyl estradiol, EE) exposure (mean total EE exposure reduction: 200 mg/day, 18%; 400 mg/day, 21%; 800 mg/day, 30%). The study reported here evaluated the TPM-OC interaction at TPM dosages most likely to be useful when used as monotherapy in, for example, newly diagnosed epilepsy and migraine prophylaxis [ndash] 50, 100, and 200 mg/day. Carbamazepine (CBZ) was used as a positive control for clinically significant effects on OC pharmacokinetics.
METHODS: In this open-label, randomized study, 48 healthy, non-obese women (BMI [lte]27 kg/m², 18-40 yrs) received TPM 50 mg/day, TPM 100 mg/day, TPM 200 mg/day, or CBZ 600 mg/day added to an OC (1.0 mg NE; 0.035 mg EE). A second TPM 200 mg/day group was comprised of 12 obese women (BMI 30-35). Two menstrual cycles were evaluated: Cycle 1, OC alone; Cycle 2, OC + TPM or CBZ. During Cycle 2, TPM and CBZ were titrated to assigned dosages by Day 12 and maintained until Day 21. Pharmacokinetic parameters determined from blood samples drawn on Day 21-22 included peak plasma concentration (C[sub]max[/sub]), time to peak concentration (t[sub]max[/sub]), area under the plasma-concentration curve during the dose interval (AUC), and oral clearance (CL/F) for NE and EE. Pharmacokinetic parameters with and without study drug were compared by ANOVA.
RESULTS: TPM did not affect NE pharmacokinetics. In CBZ-treated subjects, NE C[sub]max[/sub] and systemic exposure (AUC) were reduced 37% and 58%, respectively (p[lt]0.05). Compared with the OC alone, EE C[sub]max[/sub] with TPM coadministration changed -7% (50 mg); +5% (100 mg), -15% (200 mg non-obese) and -11% (200 mg obese); EE AUC changed -11%, +6%, -11%, and -9%, respectively. The treatment effect with TPM was not significant for C[sub]max[/sub] or AUC in any treatment group. In contrast, EE C[sub]max[/sub] was reduced 19% with CBZ co-administration (p[lt]0.05); AUC was reduced 42% (p=0.0001).
CONCLUSIONS: With TPM 50-200 mg/day as monotherapy, dose-related effects on EE pharmacokinetics were not observed, although high-dose TPM (eg, 800 mg/day) may reduce EE exposure, as demonstrated in an earlier study in women with epilepsy. As monotherapy, TPM 50-200 mg/day does not have a significant pharmacokinetic interaction with OCs.
[Supported by: Johnson & Johnson Pharmaceutical Research & Development]; (Disclosure: Salary - Johnson & Johnson Pharmaceutical Research & Development)