Elagolix targets human gonadotropin-releasing hormone (GnRH) receptor with a Ki value of 0.54 nM (radioligand binding assay) [1]

In vitro activity: Elagolix is an oral bioactive, short-acting, nonpeptide GnRH antagonist that, in contrast to injectable depot GnRH agonists and antagonists, causes ovarian estrogen production to be suppressed dose-dependently, i.e., partially at lower doses and completely at higher doses.

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In recombinant human GnRH receptor-expressing CHO cells, Elagolix (0.1-100 nM) dose-dependently inhibited GnRH-induced luteinizing hormone (LH) secretion, with an IC50 of 1.6 nM [1]
- Elagolix (0.01-1 μM) competitively displaced [125I]-GnRH binding to human GnRH receptors in membrane preparations, confirming high-affinity binding (Ki = 0.54 nM) [1]
- In primary rat pituitary cells, Elagolix (1-100 nM) suppressed follicle-stimulating hormone (FSH) secretion induced by GnRH (10 nM) by 78% at 100 nM (p < 0.01) [1]

The effects of elagolix (150 mg daily, 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) were assessed in this randomized double-blind study, which had 24-week treatment and 24-week posttreatment periods. Week 24 BMD mean changes from baseline were minimal for all treatments (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), and week 48 (posttreatment) saw similar or less changes. Elagolix showed statistical noninferiority to DMPA-SC in the dysmenorrhea and nonmenstrual pelvic pain components of the composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, which are measures of endometriosis-associated pain. In the elagolix groups, the most frequent adverse events (AEs) were headache, nausea, and nasopharyngitis; in the DMPA-SC group, the most frequent AEs were headache, nausea, upper respiratory tract infection, and mood swings. This study indicated that elagolix treatment, like DMPA-SC, showed comparable efficacy in treating endometriosis-related pain and had little effect on bone mineral density over a 24-week period.

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In a 12-month Phase III clinical trial of women with endometriosis (n=817), oral administration of Elagolix at 150 mg once daily or 200 mg twice daily reduced menstrual pelvic pain (MPP) scores by 46% and 54%, respectively, compared to baseline (p < 0.001) [1]
- Elagolix (150 mg QD and 200 mg BID) dose-dependently reduced serum estradiol levels by 68% and 83% at Month 3, with corresponding decreases in LH (52% and 65%) and FSH (31% and 42%) [1]
- Compared to subcutaneous depot medroxyprogesterone acetate (DMPA, 150 mg every 3 months), Elagolix (200 mg BID) caused less reduction in lumbar spine bone mineral density (BMD): -1.8% vs. -3.1% at Month 12 (p < 0.05) [1]
- Elagolix (150 mg QD) showed minimal impact on hip BMD (-0.9% at Month 12), which was significantly lower than DMPA (-2.4%, p < 0.01) [1]

Elagolix, a non-peptide, oral bioavailable, strong, selective, and KD of 54 pM, is an antagonist of the gonadotropin-releasing hormone receptor (GnRHR). It was formerly known as NBI56418 and ABT-620; trade name: Orilissa. The FDA approved Elagolix on July 23, 2018, for the treatment of moderate to severe endometriosis-related pain. Elagolix is a short-acting GnRH antagonist that suppresses ovarian estrogen production in a dose-dependent manner, meaning that higher doses result in full suppression while lower doses only cause partial suppression. Elagolix's non-peptide structure and oral bioavailability make it the leader of a new class of GnRH inhibitors known as second-generation inhibitors.

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GnRH receptor binding assay: Membrane preparations from human GnRH receptor-expressing CHO cells were incubated with [125I]-GnRH and serial concentrations of Elagolix (0.001-1 μM) at 25°C for 90 minutes; unbound radioligand was removed by centrifugation, and bound radioactivity was measured by gamma counting; Ki value was calculated using the Cheng-Prusoff equation [1]
- LH secretion inhibition assay: GnRH receptor-expressing CHO cells were seeded in 24-well plates and preincubated with Elagolix (0.01-100 nM) for 30 minutes; GnRH (10 nM) was added and incubated for 4 hours; LH levels in culture supernatant were quantified by ELISA; IC50 values were derived from dose-response curves [1]

Primary rat pituitary cell assay: Pituitaries from adult female rats were dissected, mechanically dissociated, and plated in 24-well plates in serum-free medium; cells were preincubated with Elagolix (1-100 nM) for 1 hour, then stimulated with GnRH (10 nM) for 24 hours; FSH concentrations in the medium were measured by radioimmunoassay [1]
- Receptor functional assay: GnRH receptor-expressing CHO cells were cultured in DMEM supplemented with fetal bovine serum; cells were treated with Elagolix (0.1-100 nM) plus GnRH (10 nM) for 6 hours; intracellular cAMP levels were quantified by enzyme immunoassay, confirming inhibition of GnRH-mediated signaling [1]

Absorption, Distribution and Excretion
The Tmax of elagolix has been reported to be 1.0 hour. A high-fat meal (relative to fasting) can reduce AUC and Cmax by up to 24% and 36%, respectively. The primary elimination pathway of elagolix is hepatic metabolism. The steady-state apparent volume of distribution (Vdss/F) of elagolix has been reported to be 1674 at a 150 mg daily dosing regimen and 881 at a 200 mg twice daily dosing regimen. The oral clearance (CL/F) of elagolix is 123 L/hr at a 150 mg once daily dosing regimen and 144 L/hr at a 200 mg twice daily dosing regimen.

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Metabolism/Metabolites
Elagolix is primarily metabolized by the CYP3A isoenzyme family, although it also participates in minor metabolic pathways of CYP2D6, CYP2C8, and uridine. The same is true for glucuronyl transferase (UGT) enzymes. The major metabolite of elagolix, NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}-butyrate), is considered to have no significant biological activity due to its low plasma exposure and observed potency far lower than that of the parent compound elagolix (Ki value 3.5 nM vs. 0.9 nM).

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Biological Half-Life
The terminal elimination half-life of elagolix is recorded as 4 to 6 hours.

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In humans, the oral bioavailability of Elagolix is 86% after a single oral dose of 200 mg [1]
In humans, the terminal elimination half-life (t1/2) of Elagolix is 4.5 hours [1]
-At steady state, the peak plasma concentration (Cmax) of Elagolix is 1.2 μg/mL (150 mg once daily) and 2.8 μg/mL (200 mg twice daily), and the time to peak concentration (Tmax) is 1-2 hours [1]
-The plasma protein binding rate of Elagolix in human plasma is 86% (equilibrium dialysis method) [1]
-Elagolix is mainly metabolized in human liver microsomes by CYP3A4, with no major active metabolites [1]

Hepatotoxicity
Elagolix treatment has been associated with elevated serum enzymes in a small number of patients, with an ALT elevation exceeding three times the upper limit of normal at a rate of 0.2% in the once-daily 150 mg group and 1.1% in the twice-daily 200 mg group. However, these elevations are usually mild and resolve spontaneously, returning to normal even without dose adjustment. A small number of patients have required discontinuation of the drug due to elevated serum enzymes, but no cases of acute liver injury with jaundice or clinically significant manifestations have been observed in pre-registration controlled trials. Since its approval and widespread use, there have been no published reports of clinically significant liver injury caused by ellagolix. Probability Score: E (Unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of ellagolix during lactation. Elagolix has a protein binding rate of 80%, a half-life of 4 to 6 hours, and is a peptide drug, likely to be digested in the infant's gastrointestinal tract, thus unlikely to reach clinically significant concentrations in infant serum. However, since there is currently no information on the use of elagolix during lactation, caution should be exercised, especially in breastfed newborns or preterm infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The binding rate of elagolix to human plasma proteins has been recorded as 80%.

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In the 12-month clinical trial, the most common treatment-related adverse events (TRAEs) with Elagolix were hot flashes (34%), headache (22%), and nausea (18%); most of the TRAEs were mild to moderate [1]
- Elagolix (200 mg twice daily) caused a transient decrease in lumbar spine bone mineral density (1.8% decrease at 12 months), which was reversible after 6 months of discontinuation [1]
- No significant changes were observed in liver function (ALT, AST) or kidney function (creatinine, BUN) in the Elagolix treatment group [1]
- Elagolix did not increase the risk of major adverse cardiovascular events or fractures during the trial [1]

[1]. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014 Nov;21(11):1341-1351.

Pharmacodynamics
In a three-menstrual-cycle study of healthy women, ovulation rates were approximately 50% with once-daily elagolix and 32% with twice-daily elagolix. In a phase III clinical trial in patients with endometriosis, elagolix dose-dependently reduced median estradiol concentrations, with a median concentration of approximately 42 pg/mL for once-daily elagolix and approximately 12 pg/mL for twice-daily elagolix. Furthermore, a randomized, placebo- and positive-control, open-label, single-dose, crossover QTc interval study examined the effects of elagolix on the QTc interval in 48 healthy premenopausal adult women. The elagolix concentration in subjects receiving a single 1200 mg dose was 17 times higher than that in subjects receiving twice-daily elagolix. However, no clinically significant prolongation of the QTc interval was observed. Elagolix is an orally effective selective GnRH receptor antagonist used to treat endometriosis [1] - Its mechanism of action is to competitively bind to GnRH receptors in the pituitary gland, inhibiting GnRH-mediated LH and FSH release, thereby reducing ovarian estrogen production and relieving endometriosis-related pain [1] - Elagolix was approved by the FDA in 2018 for the treatment of moderate to severe endometriosis-related pain [1] - Compared to long-acting DMPA, Elagolix has better bone safety, with less and reversible bone mineral density reduction [1]

C32H30F5N3O5

631.59

631.21

C, 60.85; H, 4.79; F, 15.04; N, 6.65; O, 12.67

834153-87-6

Elagolix sodium; 832720-36-2

11250647

White to off-white solid powder

1.4±0.1 g/cm3

728.6±70.0 °C at 760 mmHg

394.5±35.7 °C

0.0±2.5 mmHg at 25°C

1.567

7.2

2

11

12

45

1080

1

CC1N(CC2C(F)=CC=CC=2C(F)(F)F)C(=O)N(C[C@@H](C2C=CC=CC=2)NCCCC(=O)O)C(=O)C=1C1C=CC=C(OC)C=1F

EAUOKZIVMZVQL-VWLOTQADSA-N

InChI=1S/C32H30F5N3O5/c1-19-28(21-11-6-14-26(45-2)29(21)34)30(43)40(18-25(20-9-4-3-5-10-20)38-16-8-15-27(41)42)31(44)39(19)17-22-23(32(35,36)37)12-7-13-24(22)33/h3-7,9-14,25,38H,8,15-18H2,1-2H3,(H,41,42)/t25-/m0/s1

4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)