Comparative pharmacokinetic estimates of drospirenone alone and in combination with ethinyl estradiol after single and repeated oral administration in healthy females.

OBJECTIVE: To determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration. STUDY DESIGN: We conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4 mg or a combination of DRSP 3 mg and EE 0.02 mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log). RESULTS: A total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5 ng*h/mL, 296.1 ng*h/mL and 27.3 ng/mL for DRSP alone, and 442.0 ng*h/mL, 264.7 ng*h/mL and 37.5 ng/mL for the DRSP/EE combination; p < 0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8 ng*h/ml, 570.2 ng*h/mL and 41.0 ng/mL for DRSP alone, and 1394.5 ng*h/mL, 732.8 ng*h/mL and 61.4 ng/mL for the DRSP/EE combination; p < 0.001. CONCLUSIONS: DRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%-81.1%). This PK profile may be caused by EE. IMPLICATIONS: Our results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications.

The bioequivalence of the contraceptive steroids ethinylestradiol and drospirenone is not affected by co-administration of dehydroepiandrosterone.

OBJECTIVES: To study the effect of co-administration of 50 mg dehydroepiandrosterone (DHEA) on the bioequivalence of ethinylestradiol (EE) and drospirenone (DRSP) in women who were using a combined oral contraceptive (COC) containing 30 µg EE and 3 mg DRSP, and to estimate whether the addition of DHEA to this COC affects the serum levels and the bioequivalence of the synthetic contraceptive steroids. METHODS: This was a randomised, double-blind, two-period crossover study. Participants received two EE/DRSP COC treatment cycles in random order, one with and one without daily 50 mg DHEA , separated by a 28-day wash-out cycle during which the subjects used an EE/levonorgestrel (LNG) COC without DHEA. Serum levels of EE and DRSP were measured according to a sampling scheme allowing pharmacokinetic evaluations. RESULTS: Addition of DHEA to an EE/DRSP COC had no effect on serum levels of EE and DRSP. The COC regimens with and without DHEA were bioequivalent. Oestradiol levels were equally suppressed during pill intake, whether with placebo or DHEA. CONCLUSION: Adding DHEA to a COC containing EE and DRSP does not affect the pharmacokinetic properties of EE and DRSP. Therefore, it will most likely not affect its contraceptive efficacy.

Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study.

OBJECTIVES: The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20 µg/DRSP 3 mg. METHODS: Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6 months (Week 27) of EE 20 µg/DRSP 3 mg use. EE 20 µg/DRSP 3 mg was administered as a flexible extended regimen [24-120 days' active hormonal intake followed by 4 days with no tablet intake (tablet-free interval)], a conventional 28-day cyclic regimen (24 days' active hormonal intake followed by 4 days of placebo tablets) or a fixed extended regimen (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) over 1 year. RESULTS: The population PK of EE and DRSP in this population were successfully described using the developed population models. All three regimens led to similar steady-state drug exposure during long-term treatment. Only minor changes (≤ 8%) in the steady-state PK of EE and DRSP were observed between Week 3 and Week 27 of an extended regimen. Body weight (BW) and age had a small, statistically significant impact on the PK of EE and DRSP (BW only) in a covariate analysis, however, these changes were not considered to be clinically relevant. CONCLUSIONS: Extending the established 24/4-day regimen of EE 20 µg/DRSP 3 mg does not change the known steady-state PK of EE and DRSP, suggesting that the clinical efficacy is also similar. This is in line with the published clinical results from this study.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women.

OBJECTIVE: To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. METHOD: Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). RESULTS: In Studies 1 and 2, there was a linear dose-dependent increase in DRSP C(max) and systemic exposure across the range of doses used in both ethnic groups. The co- administration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation. There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC(0-24h) were 1.05 (90% CI: 0.95-1.17) and 1.02 (90% CI: 0.76-1.38), respectively. CONCLUSION: Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE.

[Phenogenetic analysis of testicular responsiveness to chorionic gonadotropin in inbred mouse strains].

Genetic differences in the testicular hormonal responsiveness to in vivo administration of chorionic gonadotropin (CG) between adult male mice of eight inbred strains (A/Sn, CBA/Lac, CC57Br, C57Bl/6J, DBA/2J, GR, PT, and YT) were determined. In addition, the genetic variation of the body and testis weights was estimated as related to the responsiveness to stimulation of steroidogenesis with CG. Adult males were subcutaneously injected with 10 IU of CG or physiological saline 120 min before decapitation. It was found that the baseline testosterone level in the blood serum and its content in the testes only slightly varied in males of the strains studied. Administration of CG increased these parameters by a factor of 3-45, depending on the strain. The results of the study indicate genetic differences in the testicular reactivity to CG. In addition, it has been found that the response to administration of CG, as compared to the baseline levels, provides the most reliable information on the genetic characteristics of the hormonal potential of the testes. The given set of inbred mouse strains may be a promising genetic model for studying the physiological and hereditary variations of testicular steroidogenesis.

Open labeled, uncontrolled pharmacokinetic study of a single intramuscular hCG dose in healthy male volunteers.

The current study was designed to compare blood and cerebrospinal fluid (CSF) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (hCG): Pregnyl(R), derived from human urine, and Ovitrelle(R) a recombinant form. Two separate groups, each with six older male human subjects, were dosed with either form of the drug at 10,000 IU intramuscularly (IM), and followed over a 36-hour period. No significant difference in the serum level of hCG was observed for either preparation of hCG (Peak serum conc.: 316 +/- 53 vs. 270 +/- 60 at 12 hours, 311 +/- 38 vs. 321 +/- 60 IU/l at 24 hours; AUC: 10,053 +/- 1,268 vs. 8,793 +/- 1,768, Pregnyl and Ovitrelle, mean +/- SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (CNS) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/l; range 1.9 - 2.1 and 1 - 1.4 IU/l for Pregnyl and Ovitrelle, resp.). This preliminary study in normal human volunteers suggests that the two forms of hCG tested, Ovitrelle(R) and Pregnyl(R), when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, we conclude that these two drugs demonstrate no statistical significant difference with respect to the CSF.