Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

Abstract

AIM: To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg. METHODS: In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2-4) (period 1), oral contraceptive (q24 h, days 12-32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58-60) and oral contraceptive (q24 h, days 40-60) (period 3). RESULTS: Voriconazole geometric mean AUCτ and Cmax increased 46% (12 682-18 495 ng h ml-1; 90% confidence interval [CI] 32, 61) and 14% (2485-2840 ng ml-1; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUCτ and Cmax increased 61% (1031-1657 ng h ml-1; 90% CI 50, 72) and 36% (119-161 ng ml -1; 90% CI 28, 45), respectively, and norethindrone geometric mean AUCτ and Cmax increased 53% (116-177 ng h ml -1; 90% CI 44, 64) and 15% (18-20 ng ml-1; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE. CONCLUSIONS: Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications. © 2007 Pfizer Inc.