Segesterone acetate API Manufacturers

General Description:

Segesterone acetate, identified by CAS number 7759-35-5, is a notable compound with significant therapeutic applications. Segesterone acetate is a steroidal progestin or synthetic progesterone and a 19-norprogesterone derivative with no CH3 group radical in position 6 . In animal studies, segesterone acetate was shown to be one of the most potent progestins . It mediates progestational activity 100 times higher than that of . It is commonly sold under the brand names Nestorone and Elcometrine and serves as an active component in hormonal contraceptives. It is also used as a treatment for endometriosis in South American countries. Segesterone acetate binds selectively to progesterone receptors and not androgen receptors . Due to its rapid hepatic metabolism, segesterone acetate must be administered parenterally . Segesterone acetate is not an orally active compound, but it is proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel . On August 10, 2018, Annovera™ containing segesterone acetate and was granted approval by the U.S. Food and Drug Administration (FDA) as the first and only contraceptive that provides an entire year of protection against unintended pregnancy while entirely under a woman's control. According to the Center for Disease Control, more than 43 million women in the U.S. are at risk of unintended pregnancy, which may be associated with an elevated risk for improper prenatal care, premature and low-birth-weight infants, and physical and mental health risks . The introduction of this new contraceptive method offers an expansion of birth control options for women while maintaining high efficacy and acceptability similar to existing shorter-acting combined hormonal methods . In clinical trials, Annovera™ achieved a 97.3% success in pregnancy prevention . Annovera™ is administered as a vaginal ring that is in place for 21 days and removed for 7 days each cycle. As with other hormonal contraceptives, Annovera™ carries the risk for serious cardiovascular events.

Indications:

This drug is primarily indicated for: Segesterone acetate in combination with ethinyl estradiol is indicated for use by females of reproductive potential to prevent pregnancy as a combination hormonal contraceptive (CHC). It induces contraception for thirteen 28-day cycles (1 year) following vaginal administration. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. The use in females with a body mass index of >29 kg/m^2 has not been adequately evaluated . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Segesterone acetate undergoes metabolic processing primarily in: Segesterone acetate undergoes rapid metabolism and inactivation in the liver . Based on the findings _in vitro_, the major oxidative metabolites in the serum include 5α-dihydro- and 17α-hydroxy-5α­-dihydro metabolites constitute about 50% of exposure relative to segesterone acetate. The metabolites are not pharmacologically active with EC50 to progesterone receptor 10-fold higher than that of the parent compound . It was shown that 3α, 5α-tetrahydrosegesterone acetate acts as an activator at the GABA-A receptors in the brain . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Segesterone acetate are crucial for its therapeutic efficacy: Contraceptive vaginal rings provided sustained release of contraceptive levels of segesterone acetate over 90 days in a pharmacokinetic study of healthy women . Following vaginal administration for up to 13 cycles, segesterone acetate was absorbed into systemic administration and reached the peak plasma concentration in 2 hours in Cycle 1, Cycle 3, and Cycle 13. Concentrations declined after time to reach plasma concentration (Tmax) and became more constant after 96 hours post-dose.Over subsequent cycles of use, the peak serum concentrations of segesterone acetate decreased. In Cycle 1, 3 and 13, the peak plasma concentrations were 1147, 363, and 294 pg/mL . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Segesterone acetate is an important consideration for its dosing schedule: The mean (SD) half life of segesterone acetate is 4.5 (3.4) hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Segesterone acetate exhibits a strong affinity for binding with plasma proteins: Serum protein binding of segesterone acetate is approximately 95% and it displays negligible binding affinity for sex hormone-binding globulin (SHBG) . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Segesterone acetate from the body primarily occurs through: In a pharmacokinetic study, approximately 81.4% and 7.62% of the subcutaneously-administered dose in rats was excreted via feces and urine, respectively . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Segesterone acetate is distributed throughout the body with a volume of distribution of: The volume of distribution of segesterone acetate is 19.6 L/kg . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Segesterone acetate is a critical factor in determining its safe and effective dosage: No pharmacokinetic data available. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Segesterone acetate exerts its therapeutic effects through: Segesterone acetate suppresses ovulation. In a Phase I randomized, placebo-controlled, randomized crossover study involving healthy adult female subjects, there was no clinically significant QTc interval prolongation following a single intravenous bolus dose of segesterone acetate . Segesterone acetate shows no androgenic, anabolic, or estrogenic activity . It also did not show uterotropic activity in ovariectomized rats . In the endometrial transformation test to assess the progestational activity, dose-dependent increases in both uterine weight was observed following subcutaneous administration of segesterone acetate . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Segesterone acetate functions by: Segesterone acetate selectively binds to the progesterone receptor (PR), a transcription factor belonging to the nuclear receptor superfamily, where it acts as an agonist and transactivator . According to the findings from docking experiments, it adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone but due to additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD, segesterone acetate display higher potency than progesterone . As with other progestins, segesterone acetate prevents ovulation by blocking the midcycle surge in luteinizing hormone (LH) secretion, thereby inhibiting the development of ovarian follicles . When used in combination with segesterone acetate, ethinyl estradiol potentiates the antigonadotropic of the progestin and prevents irregular shedding of the endometrium . Segesterone acetate lacks androgenic activity, and displayed binding affinity to androgen receptors that was 500- to 600-fold less than that of testosterone . It does not display binding affinity toward estrogen receptors . When the relative binding affinities of segesterone acetate to human steroid receptors were investigated _in vitro_, it was demonstrated that segesterone acetate binds to the glucocorticoid receptor . However, segesterone acetate did not exert any glucocorticoid activity in the _in vivo_ assays showing no increase in liver glycogen and tyrosine transaminase TAT . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Segesterone acetate is categorized under the following therapeutic classes: Adrenal Cortex Hormones, Contraceptive Agents, Female, Contraceptive Agents, Hormonal, Contraceptive Devices, Female, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Drug Implants, Estradiol Congeners, Estrogenic Steroids, Alkylated, Fused-Ring Compounds, Gonadal Hormones, Gonadal Steroid Hormones, Hormonal Contraceptives for Systemic Use, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Intravaginal Contraceptives, Norpregnanes, Norpregnatrienes, Norpregnenes, Norsteroids, Pharmaceutical Preparations, Pregnanes, Pregnenes, Progestins, Reproductive Control Agents, Steroids. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Segesterone acetate include:

• Water Solubility: Insoluble
• Melting Point: 173-177