In two randomized trials, two different doses of the oral gonadotropin-releasing hormone antagonist elagolix significantly reduced endometriosis-related dysmenorrhea and nonmenstrual pelvic pain but ...had hypoestrogenic adverse effects.
Elagolix is the first oral gonadotropin-releasing hormone antagonist that entered clinical development and received regulatory approval for the management of women with endometriosis and heavy ...menstrual bleeding associated with uterine fibroids in combination with a hormonal add-back therapy. This mini review aims to summarize the key clinical studies that led to its regulatory approval.
Leuprolide acetate is the first GnRH agonist that entered clinical development after the discovery of the native GnRH. Several long-acting depot formulations of leuprolide acetate (ranging from ...1-month to 6-month intramuscular injections) have been successively developed for various suppressive treatments in men, women, and children, which are available in the United States and globally. This mini review aims to summarize the key clinical studies that led to regulatory approval of leuprolide acetate depot suspension for injection.
This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg twice a day) versus subcutaneous depot ...medroxyprogesterone acetate (DMPA-SC) on bone mineral density (BMD), in women with endometriosis-associated pain (n = 252). All treatments induced minimal mean changes from baseline in BMD at week 24 (elagolix 150 mg: -0.11%/-0.47%, elagolix 75 mg: -1.29%/-1.2%, and DMPA-SC: 0.99%/-1.29% in the spine and total hip, respectively), with similar or less changes at week 48 (posttreatment). Elagolix was associated with improvements in endometriosis-associated pain, assessed with composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, including statistical noninferiority to DMPA-SC in dysmenorrhea and nonmenstrual pelvic pain components of the CPSSS. The most common adverse events (AEs) in elagolix groups were headache, nausea, and nasopharyngitis, whereas the most common AEs in the DMPA-SC group were headache, nausea, upper respiratory tract infection, and mood swings. This study showed that similar to DMPA-SC, elagolix treatment had minimal impact on BMD over a 24-week period and demonstrated similar efficacy on endometriosis-associated pain.
Objective To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E2 /progestogen add-back therapy. Design Proof-of-concept, dose-ranging, multiple-cohort study. ...Setting Forty-five US clinics. Patient(s) Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss MBL >80 mL per cycle). Intervention(s) Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg. Main Outcome Measure(s) Least-squares mean percentage change in MBL; adverse events (AEs). Result(s) Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, −72% to −98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, −8% to −41%); mean percentage changes with add-back regimens were −80% to −85%. Overall AEs were dose independent (elagolix alone, 70.0%–81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%–70.6%). Hot flush was the most common AE (elagolix alone, 45.5%–62.5%; placebo, 12.0%; add-back regimens, 18.5%–26.5%). Conclusion(s) Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. Clinical Trial Registration Number NCT01441635.
Objective To determine efficacy and safety of asoprisnil in patients with leiomyomata. Design Phase 2, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study. ...Setting Twenty-eight sites in the United States and 1 in Canada. Patient(s) One hundred twenty-nine women with leiomyomata. Intervention(s) Asoprisnil (5, 10, or 25 mg) or placebo orally daily for 12 weeks. Main Outcome Measure(s) Uterine bleeding changes by using daily bleeding diaries, hemoglobin concentrations, dominant leiomyoma and uterus volume measured sonographically, patient-reported symptoms related to bloating and pelvic pressure, endometrial thickness and morphology, hormonal parameters, and standard safety measures. Result(s) Asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of subjects at 5, 10, and 25 mg, respectively, and reduced leiomyoma and uterine volumes. Median percentage decrease from baseline in leiomyoma volume was statistically significant at 25 mg compared with placebo after 4 and 8 weeks of treatment; by week 12, leiomyoma volume was reduced by 36%. There was a significant reduction in bloating with the two highest doses and in pelvic pressure with 25 mg by week 12. Asoprisnil was associated with follicular-phase estrogen concentration and minimal hypoestrogenic symptoms. Conclusion(s) After 12-week treatment, asoprisnil controlled uterine bleeding while reducing leiomyoma volume and the associated pressure symptoms. Asoprisnil was well tolerated.
Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women.
We evaluated the pharmacokinetics and pharmacodynamics of ...elagolix.
This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit.
Elagolix 150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID) or placebo was administered for 21 days.
Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics follicle-stimulating hormone (FSH), luteinizing hormone (LH) and ovarian hormones estradiol (E2), progesterone (P), and adverse events.
Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush.
Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.
Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or ...mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17α-pentafluorethyl ...side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.
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