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

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.

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.