Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co‐administered in healthy female subjects
Authors: Andrews Emma , Damle Bharat D. , Fang Annie , Foster Grover , Crownover Penelope , LaBadie Robert , Glue Paul 
Published: February 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Voriconazole, a broad‐spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.

• Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho‐Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.

• Because co‐administration of voriconazole and Ortho‐Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two‐way pharmacokinetic interaction between these drugs.

WHAT THIS STUDY ADDS

• Although co‐administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co‐administered treatment was generally safe and well tolerated.

• It is recommended, however, that patients receiving co‐administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications.

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.