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

Abstract 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 (E2 V) and dienogest (DNG). Study Design CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E2 V 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 ( Cmax ) of E2 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 E2 V 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 Cmax of E2 and DNG on days 7 and 14 are presented. Results Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E2 Cmax 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 E2 of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean Cmax and AUC(0–24 h) of both E2 and DNG. Geometric mean ratios of Cmax and AUC(0–24 h) for E2 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 E2 V/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.