A pharmacokinetic study with a low-dose oral contraceptive containing 20 μg ethinylestradiol plus 100 μg levonorgestrel

Abstract

This study investigated the pharmacokinetics of a dose-reduced oral contraceptive containing 20 μg ethinylestradiol (EE) + 100 μg levonorgestrel (LNG) in 18 young, healthy females. Serum levels ofEE and LNG were determined after single and repeated daily oral administration over three treatment cycles, each consisting of 21 treatment days followed by a 7-day treatment-free period. Additionally,the time courses of sex hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and total and free testosterone serum levels were analyzed.Both active ingredients were rapidly absorbed andmaximum concentrations in serum were reached between, on average, 1 and 2 h after single and multiple administrations, respectively. Concentrations of EE increased during repeated daily administration.An approximate two-fold accumulation was calculated based on the comparison of EE area under the curve (AUC) (0-24 h) values determined after the first and the last tablet administration within a treatmentcycle.LNG serum concentrations also increased during repeated daily administration, reaching steady-state levels after about 11 days. Based on the comparison of AUC (0-24 h) values determined afterthe first and the last tablet administration, LNG accumulated approximately by a factor of 3 within a treatment cycle. Steady-state pharmacokinetics of LNG were similar at the end of the first and the thirdtreatment cycles, indicating no further accumulation of LNG beyond a treatment cycle under long-term use of this combined oral contraceptive.The clearance and volume of distribution of LNG decreasedand the terminal half-life increased after repeated daily administration, compared with single administration. These effects have also been reported for other LNG/EE combinations. SHBG serum concentrationsincreased during repeated daily intake by, on average, 1.5-1.6-fold, and for CBG, an average increase of 1.4-1.8-fold was found. Although free testosterone concentrations declined during repeated dailyadministration by about 40%, total testosterone remained relatively unchanged at a low level.In conclusion, the pharmacokinetics of EE and LNG determined in the present study were in good agreementwith those previously reported for 30 μg EE + 150 μg LNG, taking the 33% dose reduction into account.