A SINGLE-DOSE AND 3-MONTH CLINICAL-PHARMACOKINETIC STUDY WITH A NEW COMBINATION ORAL-CONTRACEPTIVE

The study was performed in 14 young women. The combination oral contra ceptive contained 75 mu g gestodene (GSD) and 20 mu g ethinyl estradio l (EE(2)) per dosage unit. The volunteers received a single dose on da y 21 of a treatment-free precycle (PCd21) and, after a washout period of 7 days, used the preparation in a 21 d/7 d schedule for three month s. Daily drug serum level profiles were taken on PCd21 and on days 1 a nd 21 of treatment cycles 1 and 3. In addition, trough drug serum leve ls were followed every other day during treatment cycles 1 and 3. Seru m levels of GSD, EE(2), CBG, SHBG and testosterone (T) were determined by means of specifically developed or commercially available RIAs. Ph armacokinetic evaluation was carried out with TOPFIT and parameters we re evaluated for differences with the t-test. Main target variables we re C-max, t(max) and AUC for EE(2), GSD and unbound GSD on day 21, cyc le 3 vs. PCd21. EE(2) pharmacokinetics were in agreement with a dose o f 20 mu g/unit. Single-dose C-max of 65 pg/ml and AUC of 612 pg h ml(- 1) increased by 40-60% during treatment cycles as a result of accumula tion. EE(2) induced basal SHBG (102 nmol/L) and CBG (42 mu g/ml) serum levels to about 220 nmoI/L and 87 mu g/ml, respectively, at the end o f treatment cycles 1 and 3. Serum T levels dropped to 50% of baseline levels during treatment cycles and free T concentrations were reduced by 60-70%. GSD pharmacokinetics at the end of treatment cycles 1 and 3 were different from single-dose pharmacokinetics. Single-dose C-max o f 3.5 ng/ml and AUC(0-24) h of 22 ng h ml(-1) increased to steady-stat e levels of 8-8.7 ng/ml and 90-106 ng h ml(-1), respectively. The incr ease in GSD levels under treatment is the result of two parallel proce sses, i.e. accumulation and enlargement of the specific binding compar tment. This was shown by protein-binding experiments, demonstrating an increase in specific (SHBG) binding from 69% to 80% and a reduction i n the free fraction of GSD by 40% during treatment. The results of GSD and EE(2) pharmacokinetics obtained in the present study confirm prev ious results with Femodene, when the reduction in the EE(2) dose by 10 mu g/d is taken into account.