Objective To evaluate the pharmacokinetics of a combined oral contraceptive (OC) containing oestradiol valerate/dienogest (E₂V/DNG) administered according to a four-phasic dosing regimen with an oestrogen step-down and a progestin step-up over 26 days of active treatment.

Methods This Phase I, open-label study included healthy women aged 18-50 years. Treatment consisted of the administration of E₂V 3 mg for 2 days, E₂V 2 mg/DNG 2 mg for 5 days, E₂V 2 mg/DNG 3 mg for 17 days, E₂V 1 mg for 2 days, and placebo for 2 days.

Results Pharmacokinetic data were analysed in 15 women. Stable E₂ concentrations were maintained throughout the study. Minimum mean serum E₂ levels were 33.6-64.7 pg/ml during E₂V administration. The ratio of oestrone:E₂ in serum was approximately 5:1. Minimum mean serum DNG levels were 6.8-15.1 ng/ml during DNG administration. Minimum concentrations of DNG increased only slightly during each phase of the regimen during which DNG was being administered. On day 24 the geometric mean C_max, C_ave and t of DNG were 82.9 ng/ml, 33.7 ng/ml and 12.2 hours, respectively; the median t_max was 1.5 hours. Serum sex hormone-binding globulin concentrations increased by 40% (within the normal range). Cortisol binding-globulin levels remained almost unchanged. Treatment was well tolerated.

Conclusions Treatment with an OC containing E₂V and DNG was well tolerated and was associated with stable E₂ concentrations over 28 days. The pharmacokinetics of DNG were consistent with previous findings. Minimum serum concentrations of DNG increased only slightly during phases of the regimen during which DNG was administered.