Bioequivalence study of generic tablet formulations containing ethinylestradiol and chlormadinone acetate in healthy female volunteers.

The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and chlormadinone acetate (CAS 302-22-7) (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 h post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/ml (test) and 129.12 pg/ml (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/ml (test) and 6.6663 ng/m (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/ml x h (test) and 1380.49 pg/ml x h (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/ml x h (test) and 58.111 ng/ml x h (reference). The median of tmax of ethinylestradiol was 1.5 h for both test and reference and the median of tmax of chlormadinone acetate 1.0 h (test) and 1.5 h (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 h (test) and 15.41 h (reference) and of chlormadinone acetate 56.63 h (test) and 56.17 h (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90% confidence interval for the Cmax ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of Cmax of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and Cmax fall into the generally accepted range of 80%-125%.

Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate.

BACKGROUND: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). MATERIALS AND METHODS: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. RESULTS: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. CONCLUSIONS: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.

Chlormadinone acetate (CMA) in oral contraception--a new opportunity.

Chlormadinone acetate (CMA) is a derivative of naturally secreted progesterone that shows high affinity and activity at the progesterone receptor. It has an anti-estrogenic effect and, in contrast to natural progesterone, shows moderate anti-androgenic properties. CMA acts by blocking androgen receptors in target organs and by reducing the activity of skin 5alpha-reductase. It suppresses gonadotropin secretion and thereby reduces ovarian and adrenal androgen production. CMA shows high contraceptive efficacy by inhibiting ovulation due to its ability to suppress or disrupt endogenous gonadotropin secretion and, by this, inhibits follicular growth and maturation. In addition, it suppresses endometrial thickness and increases the viscosity of cervical mucus. Pharmacokinetic studies have shown rapid and almost complete absorption after oral administration, and CMA is being bound to albumin rather than SHBG (Sex-Hormone-Binding-Globulin). Multiple dosing studies have demonstrated that steady state is reached by day 7 after oral administration with peak plasma concentrations in the region of 2 ng/ml. After a single dose of CMA the half-life time is around 34 hours and after multiple dose administration approximately 38 hours. Safety studies have indicated that CMA has no clinically relevant effect on a wide range of metabolic parameters in normal subjects. Further studies in groups at high thromboembolic risk have shown that CMA alone produces a relative risk of 0.8 which is not considered significant. These results indicated the potential for CMA to be combined with ethinylestradiol in an oral contraceptive which provides highly effective contraception and excellent cycle control.

Belara--proven benefits in daily practice.

Today, a contraceptive method is available to suit nearly every type of woman, every age and all preferences and expectations. All that seems to remain for users is to look for the right product to satisfy their personal requirements. The physician takes on the role of the adviser, responsible mainly for errors of judgement and undesirable effects. The choice of the suitable contraceptive depends on three factors: the patient profile, the profile of the method used and the user's life situation. In selecting the method of contraception, statistical measures such as the Pearl Index, rate of adverse events, risks and health benefits as well as the pharmacological profile, resulting intake modality and potential interactions should be considered. The patient profile includes both subjective wishes and standards of value relevant for world view, family planning and psychological well-being, as well as objective parameters such as age, BMI, medical history and the woman's sexual behaviour. Evaluation of these parameters by the physician is a major component of successful contraceptive counselling. Belara is a new oral contraceptive on the European market based on a monophasic combination of 2 mg chlormadinone acetate and 0.03 mg ethinylestradiol. As well as high contraceptive efficacy and a low rate of side effects, Belara features an outstanding safety profile due to its almost complete absence of mineralocorticoid and glucocorticoid action and its absent impact on hepatic metabolism. In daily practice, Belara exhibits mild antiandrogenic activity which also makes it suitable for users with antiandrogen-induced seborrhoea and moderate acne. Symptoms of PMS or unspecific dysmenorrhea and menstrual irregularities can also be alleviated or completely eliminated by taking Belara. Belara use has not been associated with any significant weight gain. In daily practice, Belara is suitable for every woman of every age without specific risk factors requiring safe contraception. Belara also has considerable additional health benefits that should also be considered when choosing a suitable contraceptive.

Metabolism of osaterone acetate in dogs and humans.

Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway.

[The relative pharmacokinetics of two oral formulations of chlormadinone acetate: Lutéran 5mg. and Lutéran tablet 10 mg]. / Etude de la biodisponibilité relative de deux formulations orales d'acétate de chlormadinone: Lutéran 5 mg et Lutéran comprimé dosé à 10 mg.

The bioavailability of a new formulation of chlormadinone acetate (one 10 mg Lutéran tablet) was compared with that of the reference formulation (two 5 mg Lutéran tablets) in a randomised crossover open trial after single oral administration of a 10 mg dose to 12 healthy female volunteers. Measurements of chlormadinone acetate plasma samples were performed by combined gas chromatography/mass spectrometry. Blood samples were collected before administration and up to 144 hours after administration. No significant difference was found between the two formulations in pharmacokinetic parameters. The bioavailability of the two formulations was equivalent in terms of time to maximum concentration (tmax [mean tmax about 2.5 h]) and area under the concentration-time curve (AUC0-infinity) [Weslake's symmetric confidence interval: 19.24%, Schuirmann two one-sided tests procedure: p < 0.05]. No difference was found between the two formulations with regard to clinical safety parameters.

Progestogens with antiandrogenic properties.

Chlormadinone acetate, cyproterone acetate and dienogest are potent, orally active progestogens, which have antiandrogenic instead of partial androgenic activity. They act mainly by blocking androgen receptors in target organs, but also reduce the activity of skin 5alpha-reductase, the enzyme responsible for converting testosterone to the more potent androgen, 5alpha-dihydrotestosterone, in sebaceous glands and hair follicles. Chlormadinone acetate and cyproterone acetate also suppress gonadotropin secretion, thereby reducing ovarian and adrenal androgen production. Combined oral contraceptives (COCs) containing antiandrogenic progestogens provide highly effective contraception (gross and adjusted Pearl indices: 0-0.7 and 0-0.3, respectively) with excellent cycle control. Furthermore, COCs containing 2mg of chlormadinone acetate or cyproterone acetate plus 30 or 35 microg of ethinylestradiol produced improvement or resolution of seborrhoea in 80% of users, acne in 59-70%, hirsutism in 36% and androgen-related alopecia in up to 86%. These COCs are generally well tolerated, the main adverse effects being nonspecific or as expected for a COC (headache, breast tenderness and nausea). They have no clinically relevant effects on metabolic or liver functions or on bodyweight. Effects on mood and libido are uncommon (<3.5% and <6% of women, respectively). COCs containing antiandrogenic progestogens are likely to be particularly valuable in women with pre-existing androgen-related disorders who require contraception. They also increase the choice of products available for women with normal skin and hair who are concerned about the possibility of developing seborrhoea or acne with other COCs.

Development of a new sensitive and specific time-resolved fluoroimmunoassay (TR-FIA) of chlormadinone acetate in the serum of treated menopausal women.

We describe the development of a serum chlormadinone acetate (CMA) time-resolved fluoroimmunoassay (TR-FIA). We prepared haptens (3-CMO-chlormadinone acetate and 6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinate), biotinylated tracers (3(biotinylaminopropylamido) 3-CMO-chlormadinone acetate and 3-(6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinylamino)1-biotinylaminopropane), and immunogens necessary for eliciting two antibodies (anti-chlormadinone acetate 3-CMO/BSA and anti-chlormadinone 20-hemisuccinate/BSA). The specificity of the assay was rigorously studied to eliminate possible interference by polar metabolites of CMA, particularly 17 alpha-acetoxy-6-chloro-3beta-hydroxypregna-4,6-diene-20-one (3beta-hydroxy metabolite), employing an easy-to-use ethylene glycol chromatographic step prior to immunoassay, so as to separate the polar metabolites, in particular the 3beta-hydroxy-CMA metabolite, from the intact CMA. The choice of the anti-CMA antibody was guided by the high assay sensitivity obtained with the anti-CMA 3-CMO/BSA antibody. The detection limit was 51pg/ml. Interassay reproducibility CVs were between 2.6 and 4.5%. This TR-FIA thus appeared to be a sensitive, specific, precise, and consequently well-suited method for measurement of serum CMA during a pharmacokinetic study in women.

Pharmacokinetics and biliary excretion of osaterone acetate, a new steroidal antiandrogen, in dogs.

The pharmacokinetics and biliary excretion of osaterone acetate (17alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA), a new steroidal antiandrogen, were investigated in intact dogs and biliary fistula dogs after bolus intravenous administration of (14)C-labeled drug. In intact dogs, OA exhibited a biexponential disposition with a very long half-life of 197.9 +/- 109.9 h. OA accounted for almost all the plasma radioactivity. The major route of excretion was in feces via the bile. One-third of the radioactivity in the bile was due to OA. The major biliary metabolite was identified as a glucuronide of 17alpha-acetoxy-6-chloro-21-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione. A significant amount of biliary recycling occurs in dogs.

[The effect of TZP-4238, an anti-androgen drug, on renal function].

The effect of TZP-4238, an antiandrogen drug, on renal function was examined. Single administration test: Patients with prostatic hypertrophy were divided according to creatinine clearance (CCr) into group A (CCr < 50 ml/min) and group B (CCr > or = 50 ml/min), and hemodynamics after a single administration of TZP-4238 were compared between the two groups. Groups A and B showed similar TZP-4238 hemodynamics, and there was no significant difference in pharmacokinetic parameters or the rate of serum protein binding between them. There was no difference in the hemodynamics of a major metabolite, 15-OH body, between the two groups. Neither was there any significant difference in the urinary excretion rate of TZP-4238 or 15-OH body. There were no findings of adverse clinical significance, and there were no problems with safety. Consecutive administration test: A 16-week consecutive administration study was performed on patients with prostatic hypertrophy associated with relative renal hypofunction. The blood levels determined in 5 patients were in good accordance with the simulation curve drawn from the results of group A. The rates of efficacy, safety and usefulness were 71.4%, 90% and 71.4%, respectively. Mild side effects were observed in one patient, but the 16-week administration was completed in all patients, and no adverse effects on renal function were observed. Favorable blood levels of TZP-4238 were obtained even in patients with prostatic hypertrophy associated with renal hypofunction, and adequate efficacy and safety were achieved even with consecutive administration. Furthermore, the drug had no apparent adverse effect on renal function.