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

ABSTRACT: 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.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.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.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.

SUBMITTER: Reif S

PROVIDER: S-EPMC3632974 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Reif Stefanie S Snelder Nelleke N Blode Hartmut H

The journal of family planning and reproductive health care 20130401 2

<h4>Objectives</h4>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&emsp14;µg/DRSP 3&emsp14;mg.<h4>Methods</h4>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 obtaine ...[more]

PMID: 23493606

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Project description:The contraceptive efficacy and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 ?g/drospirenone (DRSP) 3 mg to extend the menstrual cycle and enable management of intracyclic (breakthrough) bleeding (flexible(MIB)) was investigated and the bleeding pattern compared with a conventional 28-day regimen and a fixed extended 124-day regimen.This Phase III, 2-year, multicentre, open-label study randomly (4:1:1) allocated women (aged 18-35 years) to the following regimens: flexible(MIB) (24-120 days' active hormonal intake with 4-day tablet-free intervals); conventional (24 days' active hormonal intake followed by a 4-day hormone-free interval); or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval). Primary outcomes included the number of bleeding/spotting days during Year 1 (all regimens) and the number of observed unintended pregnancies over 2 years (flexible(MIB) only).Results were analysed in 1067 women (full analysis set). The mean number of bleeding/spotting days was lower with the flexible(MIB) vs the conventional regimen [41.0±29.1 (95% CI 38.8-43.3) vs 65.8±27.0 (95% CI 62.2-69.4) days, p<0.0001; treatment difference -24.8 (95% CI -29.2 to -20.3) days]. The corresponding value for the fixed extended regimen was 60.9±51.1 (95% CI 53.9-67.9) days. The Pearl Index for the flexible(MIB) regimen was 0.64 (95% CI 0.28-1.26). All regimens had comparable tolerability profiles.EE 20 ?g/DRSP 3 mg administered as a flexible extended regimen with MIB is effective, well tolerated and is associated with statistically significantly fewer bleeding/spotting days and fewer withdrawal bleeding episodes vs EE/DRSP in a conventional 28-day regimen. The flexible(MIB) also provided statistically significantly fewer spotting days vs EE/DRSP in a fixed extended 124-day regimen (post hoc evaluation). The flexible(MIB) regimen allows women to extend their menstrual cycle and manage their intracyclic (breakthrough) bleeding.

Project description:BackgroundDysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan.AimThe aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea.MethodsThis multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 μg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24-120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed.ResultsA total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had "very much improved" or "much improved" disease, while 54.3% and 50.9% of patients reported being "very much satisfied" or "much satisfied" with their treatment, respectively.ConclusionIn Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen.

Project description:IntroductionDysmenorrhea and endometriosis are common gynecologic disorders among women of reproductive age that significantly impact health-related quality of life (HRQL) as well as productivity. Although there are treatment options listed in Japanese guidelines, a gap remains in unmet medical needs for maximizing treatment outcome. The extended regimen of ethinylestradiol and drospirenone (EE/DRSP) (taken daily for up to 120 consecutive days) has been available in Japan for treating dysmenorrhea and/or endometriosis-associated pain since 2016. Yet, the effectiveness of its usage on HRQL has not been investigated elsewhere to date. Therefore, in this study, we aim to observe changes in HRQL of Japanese women treated with an extended regimen of EE/DRSP for dysmenorrhea and/or endometriosis-associated pain.MethodsAs part of a 2-year post-marketing surveillance study, women with dysmenorrhea or endometriosis-associated pelvic pain were prescribed extended EE/DRSP during routine clinical practice. Data were collected 1 month before and 3 and 6 months after initiating treatment. Primary outcomes were the Menstrual Distress Questionnaire (MDQ) (before, during, and after menstruation) in patients with dysmenorrhea, and the Endometriosis Impact Scale (EIS) and European Quality of Life 5-dimensions 5-level instrument (EQ-5D-5L) in patients with endometriosis.ResultsThe study cohort included 315 patients (mean age 28.9 years) with dysmenorrhea and 262 patients (mean age 31.3 years) with endometriosis. Mean MDQ total scores before and during menstruation decreased significantly after 6 months with extended EE/DRSP; there was no improvement in after-menstruation MDQ score. Mean EIS domain scores improved significantly by 6 months, with improvement in most EIS individual item scores. Mean EQ-5D-5L scores increased slightly during 6 months of treatment.ConclusionsExtended EE/DRSP treatment improved HRQL outcomes in Japanese women with dysmenorrhea or endometriosis-associated pelvic pain.Trial registrationRegistered at ClinicalTrials.gov (NCT03126747) on June 2017.

Project description:OBJECTIVE:To evaluate the effect of a digital dispenser's acoustic alarm function on adherence to ethinylestradiol (EE) 20 ?g/drospirenone 3 mg in a flexible extended regimen (EE/drospirenoneFlex) among women in five European countries (France, Germany, Italy, Spain, UK) seeking oral contraception. STUDY DESIGN:Randomized, parallel-group open-label study. METHODS:Women aged 18-35 years received EE/drospirenoneFlex administered in a regimen with cycle lengths of their choice with the aid of a digital pill dispenser over 1 year. In group A (N=250), the dispenser's acoustic alarm was activated (ie, acoustic alarm + visual reminder). In group B (N=249), the acoustic alarm was deactivated (ie, visual reminder only). In addition, the women recorded pill intake daily in diary cards. The primary efficacy variable was the mean delay of daily pill release after the dispenser reminded the woman to take a pill (reference time). Secondary efficacy variables included number of missed pills, contraceptive efficacy, bleeding pattern, tolerability, and user satisfaction. RESULTS:Dispenser data showed a mean (standard deviation [SD]) daily delay in pill release of 88 (126) minutes in group A vs 178 (140) minutes in group B (P<0.0001). Median (lower quartile, Q1; upper quartile, Q3) number of missed pills was 0 (0; 1) in group A vs 4 (1; 9) in group B (P<0.0001). Diary card results revealed similar trends; however, underreporting of missed pills was evident in both groups. No pregnancies were reported during 424 women-years of exposure. Across the two groups, the mean (SD) EE/drospirenoneFlex cycle length was 51.0 (31.8) days with strong regional differences, and the mean (SD) number of bleeding/spotting days was 50.4 (33.0) days. EE/drospirenoneFlex was well tolerated, and 80% of women were satisfied with treatment. CONCLUSION:The dispenser's activated acoustic alarm improved adherence with daily tablet intake of EE/drospirenoneFlex, reducing missed pills. EE/drospirenoneFlex provided effective contraception and a good tolerability profile.

Project description:Purpose:Dysmenorrhea negatively affects women's quality of life and poses a considerable economic burden. A recent study in Japanese patients with dysmenorrhea (NCT01892904) reported a significant reduction in the number of days with menstrual pain after treatment with a flexible extended regimen of ethinylestradiol (EE)/drospirenone (DRSP) compared with a cyclic regimen. However, individual patients' menstrual pain patterns and intensities were not indicated. Heatmapping was used to visualize menstrual pain patterns and intensities by re-evaluating the previously published data from NCT01892904. Patients and Methods:NCT01892904 was a Phase III, multicenter, randomized, open-label, active-control study of 212 women aged ?20 years randomized 1:1 to receive flexible extended or 28-day cyclic EE/DRSP treatment. Daily pain levels were recorded in patient diaries, and menstrual pain patterns and intensities were visualized using heatmapping. Patients were stratified by baseline dysmenorrhea scores and primary or secondary dysmenorrhea. Results:The heatmap data demonstrated that EE/DRSP reduced the degree of menstrual pain. Regular peaks of menstrual pain were alleviated in the extended regimen group but were still observed in the cyclic regimen group. While a decrease in the days with menstrual pain was observed in patients with higher baseline dysmenorrhea scores (5-6), those with lower baseline scores (3-4) were more likely to experience lower intensities of menstrual pain. Although pain relief was less likely in patients with secondary dysmenorrhea, those who had lower baseline dysmenorrhea scores (3-4) and received the flexible extended regimen experienced a greater reduction in the number of days with menstrual pain than those who received the cyclic regimen. Conclusion:Heatmapping effectively visualized the daily burden of menstrual pain in Japanese patients with dysmenorrhea. The analysis using heatmaps suggested that the flexible extended EE/DRSP treatment regimen was more likely to alleviate the regular occurrence of menstrual pain peaks compared with the cyclic regimen.

Dataset Information

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

Publications

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

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