Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects.
Br J Clin Pharmacol
; 65(4): 531-9, 2008 Apr.
Article
em En
| MEDLINE
| ID: mdl-18294327
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. 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 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.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Triazóis
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Hidrocarboneto de Aril Hidroxilases
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Anticoncepcionais Orais Combinados
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Citocromo P-450 CYP3A
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Oxigenases de Função Mista
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Antifúngicos
Limite:
Adolescent
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Adult
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Female
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article