Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum.

ABSTRACT

PIP: In Germany, an open, intraindividual comparative study was conducted among 14 women, 18-27 years old, to examine the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE2) during a 3-month period of treatment with a tristep oral contraceptive (OC) called Triquilar. The women first received a single oral dose of 0.125 mg LNG and 0.03 mg EE2 followed by a washout period of 1 week. They received Triquilar during 3 cycles (days 1-6, 0.05 mg LNG + 0.03 EE2; days 7-11, 0.075 mg LNG + 0.04 mg EE2; and days 12-21, 0.125 LNG + 0.03 mg EE2). The mean terminal half-life for LNG was 22 hours. Total clearance of LNG was 1 ml x min-1 x kg -1. LNG volume distribution was 128.1. At the end of the treatment cycles 1 and 3, when compared to single dose administration, the total and free LNG clearance was reduced (0.5 ml x min-1 x kg-1 and 50 ml x min-1 x kg-1, respectively). LNG volume distribution was also lower after treatment cycles than after single dose administration (52 l). LNG serum levels during Triquilar treatment accumulated by a factor of 4 when compared to the level of single dose administration. Steady-state LNG levels of around 2-3 ng/ml were achieved on day 16-18 of each treatment cycle. Sex hormone binding globulin (SHBG) levels increased by a factor of 2 when compared to pretreatment levels. This simultaneous increase in SHBG likely accounted for the changes in the pharmacokinetics of LNG. After a single dose, the free fraction of LNG was 1.4% and fractions bound to SHBG and albumin were 55% and 43.6%, respectively. At the end of cycles 1 and 3, no difference in these pharmacokinetic parameters and in the serum protein binding of LNG existed. At the end of cycles 1 and 3, the 0-4 hour area under the curve (AUC) values of EE2 increased from 298.3 to 331.2 and 369.6 pg x ml-1 x h, respectively, a 11% and 24% increase, respectively. When compared to pretreatment levels, total and free testosterone levels fell during treatment cycles 1 and 3 by around 41% and 55%, respectively.