The pharmacokinetics of sumatriptan when administered with norethindrone 1 mg/ethinyl estradiol 0.035 mg in healthy volunteers

Abstract

Background: Because the majority of migraineurs are young women in their peak reproductive years, it is important to understand the possible effects on the pharmacokinetics of both medications when sumatriptan is coadministered with an oral contraceptive (OC). Objectives: The primary objective of this study was to assess the effect of multiple dosing of the OC norethindrone 1 mg/ethinyl estradiol 0.035 mg (NE/EE) on the single-dose pharmacokinetics of sumatriptan in healthy volunteers. Secondary objectives were to determine the effect of a single dose of sumatriptan on the multiple-dose pharmacokinetics of NE and EE, and to assess the safety and tolerability of the combination. Methods: This was an open-label, 1-sequence, crossover study in healthy women who had been receiving NE/EE for at least 3 months. Subjects received 1 cycle of NE/EE, consisting of 21 days of OC and 7 days of placebo. They also received a single dose of sumatriptan 50 mg on the last day of the OC or placebo regimen. Blood samples for the determination of plasma sumatriptan concentrations were collected on days 21 and 28, and blood samples for the determination of plasma NE and EE concentrations were collected on days 20 and 21. Treatments were compared by analysis of variance. Equivalence between treatments was to be concluded if the 90% CI for the ratio of reference to test means for log e-transformed parameters (area under the plasma concentration-time curve [AUC] and maximum measured plasma concentration [C max] for each analyte fell within the interval 0.80 to 1.25. Results: Twenty-six women (mean age, 29.8 years; age range, 18–44 years; weight range, 52–82 kg) participated in the study. The 90% CI for the ratio of refence to test means for the AUC extrapolated to infinity (AUC ∞) of sumatriptan was 1.11 to 1.22, and the 90% CIs for the AUC over the dosing interval at steady state (AUC τ) of NE and EE were 0.96 to 1.00 and 0.91 to 0.97, respectively. The 90% CIs for the ratio of reference to test means for the C max of sumatriptan, NE, and EE were a respective 1.05 to 1.30, 0.76 to 0.88, and 0.88 to 1.04. Study treatments were well tolerated. Adverse events were mild or moderate, and there were no clinically significant changes in vital signs or laboratory values. Conclusions: The extent of absorption (AUC) of sumatriptan, NE, and EE was similar after oral administration of sumatriptan and NE/EE, both alone and in combination. Thus, in the opinion of the study investigators, there were no clinically relevant changes in the AUC of any of the medications when sumatriptan and NE/EE were administered concomitantly compared with administration alone. The results of this study suggest that dose adjustment is not necessary when sumatriptan is administered concomitantly with NE/EE in healthy premenopausal women.