Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women

Background: We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E2V) and dienogest (DNG). Study Design: CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E2V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC((0-24 h))] and maximum serum concentration (C-max) of E-2 and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E2V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC((0-24 h)) and C-max of E-2 and DNG on days 7 and 14 are presented. Results: Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E-2 C-max and AUC((0-24 h)) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E-2 of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C-max and AUC((0-24 h)) of both E-2 and DNG. Geometric mean ratios of C-max and AUC((0-24 h)) for E-2 were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively. Conclusions: Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E2V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable. (C) 2012 Elsevier Inc. All rights reserved.