Pearl Index study with levonorgestrel-releasing intravaginal rings: using pharmacokinetic results to investigate treatment compliance as a potential contributor for contraceptive failure.

STUDY QUESTION: What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)? SUMMARY ANSWER: The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI). WHAT IS KNOWN ALREADY: Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 µg LNG per day. STUDY DESIGN, SIZE, DURATION: The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18-35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan). MAIN RESULTS AND THE ROLE OF CHANCE: The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries. LIMITATIONS, REASONS FOR CAUTION: The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Bayer AG and all authors are employees of Bayer AG. TRIAL REGISTRATION NUMBER: NCT02403401.

Effects of a combined oral contraceptive containing oestradiol valerate/dienogest on hormone withdrawal-associated symptoms: results from the multicentre, randomised, double-blind, active-controlled HARMONY II study.

The objective of this multicentre, randomised, double-blind study was to compare a combined oral contraceptive (COC) containing oestradiol valerate/dienogest (E2V/DNG) administered in a dynamic dosing regimen with a monophasic COC containing ethinyloestradiol/levonorgestrel (EE/LNG), with regard to their ability to reduce the frequency and intensity of headache and pelvic pain in women with hormone withdrawal-associated symptoms (HWAS). Women aged 18-50 years received E2V/DNG in an oestrogen step-down and progestin step-up regimen (26/2 regimen; n = 223) or EE 20 µg/LNG 100 µg (21/7 regimen; n = 218) over six cycles. Headache and pelvic pain were assessed using a visual analogue scale (VAS) during cycle days 22-28. Rescue medication use was also assessed. E2V/DNG was superior to EE/LNG with regard to reducing the frequency and intensity of headache and pelvic pain from baseline to cycle 6 (change from baseline in the average of the three highest VAS values [mean ± standard deviation]: 47.7 ± 29.4 vs 34.5 ± 25.7 mm, respectively; p < 0.0001). The use of rescue medication was also significantly reduced with E2V/DNG compared with EE/LNG (p < 0.05). E2V/DNG may be a good option for women who experience HWAS with traditional 21/7-day regimen COCs.

Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial.

BACKGROUND: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E(2)V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology. METHODS: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E(2)V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90-day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. RESULTS: The intention-to-treat population comprised 231 women. The E(2)V/DNG response rate was much higher than with placebo (P < 0.0001). The mean reduction in MBL volume in E(2)V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E(2)V/DNG (95% confidence interval 490, 255 ml; P < 0.0001). Significant improvements in iron metabolism parameters were observed with E(2)V/DNG but not placebo. Overall, 14 women (9.7%) treated with E(2)V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E(2)V/DNG and placebo groups (each n = 2). CONCLUSIONS: E(2)V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E(2)V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801.

Effects of combined oral contraceptive ethinylestradiol (30 microg) and dienogest (2 mg) on carbohydrate metabolism during 1 year of conventional or extended-cycle use.

The effects of extended regimens of combined oral contraceptives (COCs) on carbohydrate metabolism are largely unknown. The present study compared the effects of a COC containing 30 microg ethinylestradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year. Parameters of carbohydrate metabolism were measured in 59 women treated with EE/DNG either conventionally (13 cycles of 21+7 days) or in extended-cycle regimen (4 cycles of 84+7 days). Blood samples were taken in a control cycle, and at 3 and 12 months of treatment. The mean levels of HbA1c and fasting glucose levels remained stable in both conventional and extended-regimen of EE/DNG. The mean levels of fasting insulin and C-peptide underwent comparable increases in both regimens, suggesting a similar readjustment of glucose metabolism via slightly increased insulin secretion. For both regimens, the response to the oral glucose tolerance test (OGTT) showed a slightly impaired glucose tolerance and insulin resistance at 3 months. These changes improved or returned to baseline at 12 months. Accordingly, the mean index for insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR) increased and the mean insulin sensitivity index [ISI (composite)] decreased modestly in both groups. The present study demonstrates that there are no statistically significant differences between the effects of conventional and extended-cycle treatment on carbohydrate metabolism over 1 year of treatment. In general, the effects of both regimens were moderate and mostly transient.

Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism.

OBJECTIVE: To assess the efficacy and safety of a novel long-acting im testosterone undecanoate (TU) formulation in comparison with testosterone enanthate (TE). SUBJECTS AND METHODS: An open-label, randomized, prospective clinical trial in 40 hypogonadal men (baseline serum testosterone levels <5 nmol/l), randomly assigned to 250 mg TE/3 weeks (no.=20) or 1000 mg TU im every 6 to 9 weeks for 30 weeks (no.=20). Subsequently, 32/40 men continued the study for another 114 weeks, now receiving TU 1000 mg/12 weeks. RESULTS: TU and TE produced no statistically significant improvements in grip strength over the first 30 weeks, which only occurred after approximately 90 weeks when all subjects received TU. There were no changes in body mass index with TU and TE, neither in the follow-up period when all patients received TU. But ratios of waist to hip circumferences declined in the longer term. Total serum cholesterol, LDL cholesterol, and triglycerides declined over the first 30 weeks, while plasma HDL also declined. Plasma LDL decreased further under long-term TU therapy, while HDL then increased. Hemoglobin and hematocrit values significantly increased over the first 30 weeks in both treatment groups and then no further increase was observed. Levels did not exceed the upper limit of normal. In both treatment groups, serum prostate specific antigen levels rose slightly after 30 weeks, with no further increase over the first 12 months, remaining stable within the normal range. Plasma T before the following TU injection was above the lower limit of reference values. Four injections per year are adequate. CONCLUSIONS: Administration of TU every 12 weeks is at least as safe and efficacious for treatment of hypogonadal men as TE, with a substantially lower frequency of administration. Follow-up over 114 weeks, when all subjects received TU, showed an excellent profile of efficacy and safety.

A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate.

INTRODUCTION: This is a four-year follow-up of 25 men who received parenteral testosterone undecanoate (TU), 1000 mg every 12 weeks for at least four years. This study was a continuation of a 30-week study wherein the effects of TU had been compared to those of parenteral testosterone enanthate. METHODS & RESULTS: Plasma testosterone (T) trough values of the injection interval of 12 weeks): median 11.9 - 15.9 nmol/L (N 10.0-30.0). E2 and SHBG were stable. Body weight, BMI, waist-to-hip ratio remained stable. Total cholesterol, and triglycerides were unchanged but plasma LDL declined while HDL, after an initial reduction over the first 30 weeks, had increased significantly after three years. Leptin levels, bone mineral density, blood pressure, liver function tests, haemoglobin and haematocrit levels remained stable without values above the upper limit of normal. Over the first 12 months of the study there was an increase in prostate volume from 19.7 +/- 8.8 mL to 22.0 +/- 8.4 mL (p < 0.05) but thereafter volumes remained stable, paralleled by an increase in PSA from 0.67 +/- 0.38 microg/dL to 0.75 +/- 0.35 microg/dL (p < 0.05) without any further changes after 12 months. CONCLUSION: TU appears to be a stable and safe treatment modality of hypogonadal men.

Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism.

In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate (TU) formulation in 40 hypogonadal men (serum testosterone concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive either 10 x 250 mg T enanthate (TE) im every 3 wk (n = 20) or 3 x 1000 mg TU im every 6 wk (loading dose) followed by 1 x 1000 mg after an additional 9 wk (n = 20). In a follow-up study, observation continued in those patients who completed the comparative part and opted for TU treatment (8 x 1000 mg TU every 12 wk in former TU patients and 2 x 1000 mg TU every 8 wk plus 6 x 1000 mg every 12 wk in former TE patients) for an additional 20-21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study groups. In the TE group, mean trough levels of serum T were always less than 10 nmol/liter before the next injection, whereas in the TU group, mean trough levels of serum T were 14.1 +/- 4.5 nmol/liter after the first two doses (6-wk intervals) and 16.3 +/- 5.7 nmol/liter after the 9-wk interval at wk 30. The mean serum levels of dihydrotestosterone and estradiol also increased in parallel to the serum T pattern and remained within the normal range. In the follow-up study, the former TU patients (n = 20) received eight TU injections at 12-wk intervals, and the TE patients (n = 16) switched to TU and initially received two TU injections at 8-wk intervals (loading) and continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough levels of T (ranging from 14.9 +/- 5.2 to 16.5 +/- 8.0 nmol/liter) and estradiol (ranging from 98.5 +/- 45.2 to 80.4 +/- 14.4 pmol/liter). The present study has shown that 1000 mg TU injected into male patients with hypogonadism at 12-wk intervals is well tolerated and leads to T levels within normal ranges, using four instead of 17 or more TE injections per year. An initial loading dose of either 3 x 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 x 1000 mg TU every 8 wk after switching from the short-acting TE to TU were found to be a adequate dosing regimens for starting of treatment with the long-acting TU preparation.

Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters.

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on thyroid hormone parameters, cortisol, aldosterone, endothelin-1 and angiotensin II was investigated. Four groups composed of 25 volunteers each (ages between 18 and 35 years) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken by venipuncture after at least 12 h fasting on Day 21-26 of the control cycle and on Day 18-21 of the first, third and sixth treatment cycle. There was a significant increase in triiodothyronine (T3) and thyroxine (T4) by 20-40% in all treatment cycles, while thyroid-stimulating hormone was significantly increased only with EE/EV/DNG. Treatment with the DNG-containing OCs caused no change in free T4 (FT4) and a transitory reduction in free T3 (FT3) levels during the first cycle. During intake of EE/LNG, FT4 rose slightly, while FT3 was not altered. The pronounced rise in the serum concentrations of cortisol appeared to be related to the EE dose. During the first three cycles of treatment, no effect on angiotensin II levels was observed, while in the sixth cycle a significant decrease was measured in all treatment groups. The four OCs did not influence the serum concentrations of endothelin-1 and no consistent effects were found concerning those of aldosterone. The results suggest that the three DNG-containing and the LNG-containing low-dose OCs may increase T3, T4 and cortisol due to an elevated binding to serum globulins, while the free proportion of the hormones is not or only slightly changed. Therefore, these OCs have only minor effects on thyroid function, adrenal and blood pressure serum parameters.

Effect of four different oral contraceptives on various sex hormones and serum-binding globulins.

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on various hormone parameters and serum-binding globulins was investigated. Four groups with 25 volunteers each (18-35 years of age) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken after at least 12 h of fasting on Day 21-26 of the preceding control cycle and on Day 18-21 of the first, third and sixth treatment cycle. The serum concentrations of free testosterone were significantly decreased by about 40-60% in all four groups, while those of dehydroepiandrosterone sulfate (DHEAS) showed a time-dependent decrease during treatment. Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations. There was a significant increase in the levels of serum-binding globulins during treatment, which differed according to the composition of the OCs used. The rise in sex hormone-binding globulin (SHBG) was highest during intake of 30EE/DNG (+320%) and lowest with EE/LNG (+80%), while the effect of 20EE/DNG and EE/EV/DNG was similar (+270%). The thyroxine-binding globulin (TBG) levels increased significantly, by 50-60%, during treatment with the DNG-containing formulations, while the effect of EE/LNG was less significant (+30%). The rise in corticosteroid-binding globulin (CBG), which occurred in all groups, was most pronounced in women treated with 30EE/DNG (+90%) and least with EE/EV/DNG (+55%), indicating a strong influence of EE and no effect of the progestogen component. In all treatment groups, the frequency of intracyclic bleeding rose in the first treatment cycle and decreased thereafter. Cycle control was significantly better with 30EE/DNG or EE/LNG than with 20EE/DNG or EE/EV/DNG. There was no significant change in blood pressure, body mass index or pulse rate throughout the study. In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation. The effects on CBG suggest a lesser hepatic effect of 2 mg EV as compared to 20 or 30 microg EE. In contrast to EE, the use of estradiol in OCs appeared to increase prolactin release, while the cycle control was better with the OC containing 30 microg EE.

Effect of dienogest-containing oral contraceptives on lipid metabolism.

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on lipid metabolism was investigated. Four groups composed of 25 volunteers each (mean age 26.1 +/- 4.5 years; body mass index 21.9 +/- 2.8 kg/m(2)) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinyl estradiol (EE) + 2 mg dienogest (DNG) (30 EE/DNG), 20 microg EE + 2 mg DNG (20 EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG), or 20 microg EE + 100 microg levonorgestrel (LNG; EE/LNG). The study was completed by 91 women. Blood samples were taken by venipuncture after at least 12 h fasting on Days 21-26 of the control cycle and Days 18-21 of the first, third, and sixth treatment cycle. There were clear differences between the effects of EE/LNG and the formulations containing estrogens and DNG. Although EE/LNG did not change the triglycerides levels, a significant increase was observed during treatment with the DNG-containing preparations. Although EE/LNG significantly reduced HDL-CH and HDL(2)-CH, there was a nonsignificant increase with the DNG-containing OCs. No change was observed in the levels of HDL(3)-CH. A significant rise in apolipoprotein A1 occurred during intake with the three DNG-containing formulations, but not with EE/LNG. In contrast to the women treated with combinations of estrogens and DNG, apolipoprotein B rose significantly in the women in the EE/LNG group. Lipoprotein (a) was significantly reduced by 30 EE/DNG and EE/LNG and remained unaltered with 20 EE/DNG and EE/EV/DNG. Altogether, the changes in lipid metabolism caused by the DNG-containing formulations appeared to be more favorable than those observed with EE/LNG. In OCs with DNG, the EE dose does not seem to play a major role with respect to the effect on lipids.

Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest - a dose-ranging study.

OBJECTIVES: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. METHODS: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. RESULTS: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. CONCLUSIONS: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.

A comparative study of the effects of two oral contraceptives containing dienogest or desogestrel on the human immune system.

The effects of two oral contraceptive combinations, dienogest 2.0 mg plus ethinyl estradiol 0.03 mg (Valette) and desogestrel 0.15 mg plus ethinyl estradiol 0.02 mg (Lovelle), on the human immune system were compared over one treatment cycle of 31 patients (n = 15 and n = 16, respectively). Lovelle but not Valette significantly increased the numbers of lymphocytes, monocytes and granulocytes. Valette decreased CD4 lymphocytes after 10 days' treatment; Lovelle had the opposite effect. Lovelle increased CD19 and CD23 after 21 days' treatment. Phagocytic activity was unaffected by either treatment. After 10 days' treatment, both contraceptives reduced serum IgA, IgG and IgM, which remained lowered at day 21 with Lovelle but returned to baseline with Valette. Secretory IgA was unaffected by either contraceptive. Neither treatment affected levels of interleukins, except for a significant difference between the treatment groups for interleukin-6 after 10 days' treatment that disappeared after 21 days' treatment. Levels of non-immunoglobulin serum components fluctuated; macroglobulin was increased with Valette. However, total protein and albumin levels were reduced more with Lovelle than with Valette. Complement factors also fluctuated. There was no evidence for any sustained immunosuppression with either Valette or Lovelle.

Pharmacokinetics of orally administered estradiol valerate. Results of a single-dose cross-over bioequivalence study in postmenopausal women.

A randomized, single-dose cross-over study in 32 postmenopausal women was performed to demonstrate bioequivalence of two estradiol valerate containing formulations (first sequence of Klimonorm as test preparation). The serum levels of estradiol, free and conjugated estrone were measured until 48 h after an oral dosage of 4 mg estradiol valerate (CAS 979-32-8). The mean AUC(0-48) of estradiol was calculated as 1006.6 +/- 479.4 h x pg x ml-1 (Test) and 1015.2 +/- 555.2 h x pg x ml-1 (Reference). The corresponding (AUC(0-48) of the active metabolite, free estrone, exceeded that of estradiol at 3578.3 h x pg x ml-1 (Test) and 3485.1 h x pg x ml-1 (Reference). Much higher was the AUC(0-48) for conjugated estrone at 132.4 h x ng x ml-1 (Test) and 133.6 h x ng x ml-1 (Reference). Mean estradiol Cmax values of 39.8 +/- 17.7 pg/ml (Test) and 42.9 +/- 21.0 pg/ml (Reference) were attained 8.2 +/- 4.5 h (Test) and 10.0 +/- 5.9 h (Reference) after the administration of 4 mg estradiol valerate. Maximal free estrone concentrations of 163 pg/ml (Test) and 174.3 pg/ml (Reference) were reached after 7.2 h (Test) and 7.5 h (Reference). Maximal conjugated estrone concentrations of 15.5 ng/ml (Test) and 16.2 ng/ml (Reference) were reached after 2.4 h (Test) and 2.0 h (Reference). The terminal elimination half-life of estradiol was calculated at 16.9 +/- 6.0 h (Test) and 15.0 +/- 4.8 h (Reference), that of free estrone at 16.3 h (Test) and 13.5 h (Reference), that of conjugated estrone at 11.8 h (Test) and 10.6 h (Reference). After logarithmic transformation, the 90% confidence intervals of the AUC(0-48) and Cmax ratios for estradiol and also for the metabolites (free and conjugated estrone) were within the acceptance ranges for bioequivalence. Therefore the test preparation and the reference preparation are bioequivalent.

Evaluation of an oral pulsatile delivery system for melatonin in humans.

Using melatonin (MT) as a circadian synchroniser in humans to treat a variety of rhythm disorders, it is desirable to develop controlled-release dosage forms that deliver MT in accordance with its endogenous secretory pattern as well as preparations that release MT in a pulsatile way. In this paper we describe two oral pulsatile dosage forms containing 10 mg MT each (capsules B and C) and a fast-release form containing 5 mg MT (capsule A) studied in a randomised single-dose, threefold cross-over study in 15 healthy male volunteers. The concentrations of both MT in serum and its main metabolite 6-sulfatoxymelatonin (aMT6s) in urine were analysed by means of specific radioimmunoassays up to 10 h p.a. of the MT preparations. Mean peak concentrations of MT in serum were reached between 0.5 h and 0.75 h (Cmax[1] pmol/ml): 20.7 (A), 16.4 (B), 9.7 (C). The capsules B and C released a second MT pulse after about 3.5 h with Cmax[2] of 13.0 and 17.5 pmol/ml, respectively. Dose proportionality for the MT preparations studied was calculated by determining the AUC0-infinity (pmol/ml.h): 18.4 (A), 36.1 (B), 42.4 (C). The terminal serum half-lives of MT ranged between 0.64 and 0.84 h. The time course of the renally excreted aMT6s correlated with that of changes in MT serum concentrations.

Can oral contraceptive steroids influence the elimination of nifedipine and its primary pryidine metabolite in humans?

OBJECTIVE: To investigate the influence of oral contraceptives on cytochrome P450 3A4 (P450NF) activity. METHODS: In 23 healthy women, the pharmacokinetics of nifedipine and its main metabolite dehydronifedipine in plasma were assessed after a single oral dose, prior to and after intake of one of two oral contraceptive formulations, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). RESULTS: While the intake of two oral contraceptives for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine, mean AUC0-23.5 h and the mean Cmax values of dehydronifedipine were significantly lower in both groups tested/(24% in group A and 25% in group B). This observation may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. The activation of the same or other metabolic degradation mechanism(s) could explain this result. CONCLUSION: The investigation presented demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing ability.

PIP: The influence of combined oral contraceptives (OCs) on cytochrome P450 3A4 activity was investigated in a study of 23 healthy women. The pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in plasma were measured after a single oral dose, before and after intake of 1 or 2 OC formulations. The first contained 2 mg of dienogest and 0.03 mg of ethinyl estradiol (group A); the second contained 0.125 mg of levonorgestrel and 0.03 mg of ethinyl estradiol (group B). OC use for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine. However, the mean area-under-curve values at 0-23.5 hours after nifedipine administration were significantly lower than baseline (by 24% in group A and 25% in group B). This finding may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. Activation of the same or other metabolic degradation mechanisms could explain this finding. Assessment of its clinical importance requires a longer period of nifedipine use. This study demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing activity.

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

Double-blind, randomized, placebo controlled study on the effects of the monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 2.00 mg dienogest on the hemostatic system.

Forty healthy female volunteers aged between 19 and 35 years (27.3 +/- 4.1 years) with normal menstrual cycles were included in a double-blind, randomized, placebo-controlled study to investigate the influence on the hemostatic system of an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest, which is a 19-norprogestin without a 17 alpha-ethinyl group. At baseline and during one treatment cycle, 12 hemostatic parameters were measured on cycle days 7, 14, and 21. The hemostatic parameters were categorized as either procoagulatory, anticoagulatory and profibrinolytic, or antifibrinolytic and indicative of fibrin turnover. Differences between placebo and 30 micrograms ethinyl estradiol and 2.00 mg dienogest of plasma levels of hemostatic parameters on cycle days 21 of the precycle and treatment cycle were chosen as target variables. Prothrombin fragment 1 + 2 (F 1 + 2) was chosen as the main target variable. Equivalence of F 1 + 2 between placebo and active treatment was noted. Among the procoagulatory factors, only factor VII activity was found to be increased over placebo in the active treatment group, but decreased in the placebo group. Protein C activity increased during the treatment with 30 micrograms ethinyl estradiol and 2.00 mg dienogest, and was higher than that of the placebo group in which this parameter decreased during the treatment cycle. There was a corresponding increase in fibrinolytic activity being reflected by higher plasminogen levels in the active treatment group in comparison with placebo. An increase was noted for the fibrinolytic parameter D-dimer. Apart from isolated measurements, the parameters remained in their respective normal ranges. The data combine to suggest that 30 micrograms ethinyl estradiol and 2.00 mg dienogest has a balanced effect on the hemostatic system stimulating both procoagulatory and fibrinolytic activity.

PIP: The influence on the hemostatic system of a monophasic oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 2 mg of the progestin dienogest was investigated in a double-blind, placebo-controlled study involving 40 healthy German women 19-35 years old. A total of 12 hemostatic parameters were measured on cycle days 7, 14, and 21 at baseline and during 1 treatment cycle. The prothrombin fragment 1 + 2 (an early and sensitive marker for the activation of hemostasis) was equivalent between OC users and untreated controls. Among the precoagulatory factors, only factor VII activity was not equivalent; on day 21, there was a decrease in the placebo group and an increase in the OC group. Also on day 21 of the treatment cycle, protein C activity increased in OC users compared to controls. There was a corresponding increase in fibrinolytic activity, reflected by higher plasminogen levels in OC users, and an increase in the fibrinolytic parameter D-dimer. In general, hemostatic parameters remained within their normal ranges. These findings confirm that the OC analyzed has a balanced effect on the hemostatic system, simultaneously stimulating both procoagulatory and fibrinolytic activity.

Bioavailability study with 2 different levonorgestrel-containing drugs in women.

In a randomized, single dose, open crossover study in 24 healthy women, aged between 20 and 28 years, the relative bioavailability of the test product Mini 30 (0.03 mg levonorgestrel) in comparison to a reference, Microval, was investigated after single dose administration. Because there was a difference in the in vitro dissolution test, it was of interest whether this difference had an influence on the extent and rate of absorption. Whereas 99.4% of the test were dissolved after 20 minutes, only 48.3% of the reference were dissolved after 45 minutes, 74.8% after 120 minutes and 95.5% after 240 minutes. Blood samples were taken from time 0-72 hours after administration. All serum samples were analyzed twice in a radioimmunoassay which was validated before the start of the study. The limit of quantitation was at 50 pg/ml. The AUC0 -infinity ratio test/reference and the 90% confidence interval were 104.8%, and 99.10%, respectively. The Cmax ratio test/reference and the 90% confidence interval were 175.5%, and 159.8%-192.8%, respectively. With regard to the extent of absorption (AUC0-infinity) the 2 preparations were within the acceptance range for bioequivalence whereas they were outside the acceptance range for the rate of absorption (Cmax). The elimination half-lives of LNG did not differ between the test and reference preparations (25.08 +/- 11.94 h, and 25.70 +/- 10.08 h, respectively). So, the in vitro results concerning the rate of dissolution were confirmed by the in vivo findings in Cmax whereas regarding the extent of absorption (AUC) there were no differences between the 2 preparations.

[Effect of ethinyl estradiol-dienogest combination on serum androgen concentrations]. / Der Einfluss einer Ethinylestradiol-Dienogest-Kombination auf die Serum-Androgen-Konzentrationen.

Antiandrogens or progestins with an antiandrogenic component usually have only a weak antigonadotropic activity. It is thus possible that the antiandrogenic effect on the cellular level is cancelled or at least reduced by an increased ovarian androgen production. The aim of the four submitted clinical studies of the progestin and antiandrogen dienogest alone (0.5-2 mg/day) or of a combined regimen of ethinylestradiol (0.03 mg) plus dienogest (2 mg) (EE/DNG) was to examine the influence on the serum androgen and SHBG concentrations as well as on the serum FSH, LH, progesterone and 17 beta-estradiol concentrations in young women. Like the progesterone derivatives, dienogest has a relatively low antigonadotropic activity. Inhibition of ovulation is mainly produced by peripheral mechanisms such as the reduction of preovulatory 17 beta-estradiol secretion. Dienogest alone has no significant effects on the serum SHBG and androgen concentrations. Unlike this, the combination of EE plus DNG markedly increases SHBG concentrations (to 2.1-3.7 fold the basal levels). The decrease in serum androgens with total testosterone (by 17 and 40%), free testosterone (by 48 and 54%) and dehydroepiandrosterone sulfate (by 51%) corresponds to the values shown in the literature for other oral contraceptives with modern progestins. EE/DNG does not affect the serum concentrations of 5 alpha-dihydrotestosterone (DHT), although the marker of the peripheral transformation from T to DHT, androstanediol glucuronide, is distinctly reduced (by 38%). In a double-blind comparison no differences are found between EE/DNG and a regimen combining 0.02 mg of ethinylestradiol and 0.150 mg of desogestrel. Solely the SHBG concentrations, with EE/DNG, as expected, are significantly higher. In a sequential regimen, dienogest, chlormadinone acetate and desogestrel (progestins without binding to SHBG) enhance the inhibitory effect of ethinylestradiol sulfonate on free testosterone, whereas norethindrone acetate and levonorgestrel (progestins with a strong binding to SHBG) reduce this effect of the estrogen significantly. These results exclude the possibility that the very distinct antiandrogenic effect of dienogest on a cellular level is neutralised or reduced by an increased systemic supply of androgen.