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


CONCLUSIONS
* 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.


OBJECTIVE
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 microg.


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 AUC(tau) and C(max) 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 AUC(tau) and C(max) 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 AUC(tau) and C(max) 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.
Andrews
Emma
E
Pfizer Inc., New York, NY 10017, USA.
Damle
Bharat D
BD
Fang
Annie
A
Foster
Grover
G
Crownover
Penelope
P
LaBadie
Robert
R
Glue
Paul
P
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007527:Isoenzymes; D013058:Mass Spectrometry / Q000379:methods; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole
D000935:Antifungal Agents; D003277:Contraceptives, Oral, Combined; D007527:Isoenzymes; D011743:Pyrimidines; D014230:Triazoles; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole