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Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2008 Apr; Vol. 65 (4), pp. 531-9. Date of Electronic Publication: 2008 Feb 21. - Publication Year :
- 2008
-
Abstract
- 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.<br />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.<br />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 microg.<br />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).<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Antifungal Agents administration & dosage
Antifungal Agents adverse effects
Contraceptives, Oral, Combined administration & dosage
Contraceptives, Oral, Combined adverse effects
Cytochrome P-450 CYP2C19
Dose-Response Relationship, Drug
Drug Interactions physiology
Epidemiologic Methods
Female
Humans
Isoenzymes
Mass Spectrometry methods
Pyrimidines administration & dosage
Pyrimidines adverse effects
Treatment Outcome
Triazoles administration & dosage
Triazoles adverse effects
Voriconazole
Antifungal Agents pharmacokinetics
Aryl Hydrocarbon Hydroxylases metabolism
Contraceptives, Oral, Combined pharmacokinetics
Cytochrome P-450 CYP3A metabolism
Mixed Function Oxygenases metabolism
Pyrimidines pharmacokinetics
Triazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 65
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 18294327
- Full Text :
- https://doi.org/10.1111/j.1365-2125.2007.03084.x