Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects.
OBJECTIVE
To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure.


METHODS
This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2.


RESULTS
Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated.


CONCLUSIONS
TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.
Doose
Dennis R
DR
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey, USA.
Wang
Shean-Sheng
SS
Padmanabhan
Mukund
M
Schwabe
Stefan
S
Jacobs
David
D
Bialer
Meir
M
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D019540:Area Under Curve; D015992:Body Mass Index; D002220:Carbamazepine / Q000494:pharmacology*; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000097:blood; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008656:Mestranol / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009640:Norethindrone / Q000493:pharmacokinetics*; D009765:Obesity / Q000097:blood*; D000077236:Topiramate
D000927:Anticonvulsants; D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D004997:Ethinyl Estradiol; C014715:Norinyl; D003577:Cytochrome P-450 Enzyme System; D008656:Mestranol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009640:Norethindrone