GnRHR

Degarelix, among the LHRH antagonists Cetrorelix (HY-P0009), Abarelix (HY-13534), and Ganirelix (HY-P1628), exhibits the least amount of histamine release and the weakest histamine-releasing properties[1]. Except for PC-3 cells, degarelix (1 nM-10 μM, 0-72 h) decreases cell viability in all prostate cell lines (WPE1-NA22, WPMY-1, BPH-1, and VCaP cells)[2].
Degarelix (10 μM, 0-72 h) uses apoptosis to directly affect the growth of prostate cells[2].

Degarelix (0-10 μg/kg; s.c.; once) reduces plasma levels of testosterone and LH in castrated rats in a dose-dependent manner[3].
Degarelix is stable when incubated in microsomes and cryopreserved hepatocytes from animal liver tissue. In rats and dogs, the majority of the degarelix dosage is excreted in the urine and feces in equal proportions (40–50% in each matrix) within 48 hours, while in monkeys, the main excretion routes are the feces (50%) and the kidneys (22%)[4].

Assay for Cell Viability [2]
Cell Lines: VCaP, LNCaP, BPH-1, WPMY-1, and WPE1-NA22
Percentage: 1 nM-10 μM
Incubation Time: WPMY-1 cells at 48 and 72h, WPE1-NA22 cells at 72 hours, BPH-1 cells at 48 and 72h, LNCaP cells at 48 and 72h
Result: Reduced cell viability in all prostate cell lines, with the exception of the PC-3 cells.

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Apoptosis Analysis[2]
Cell Line: WPE1-NA22, BPH-1, LNCaP and VCaP
Concentration: 10 μM
Incubation Time: 24, 48 and 72 h
Result: Induced a significant increase on caspase 3/7 activation.

Male Sprague-Dawley rats, castrated
0.3, 1, 3 and 10 μg/kg or 12.5, 50, and 200 μg/kg
Subcutaneous injection, once

Absorption, Distribution and Excretion
Following subcutaneous injection, degarelic forms a drug reservoir at the injection site, from which the drug is slowly released into the bloodstream. After a single intravenous bolus of 2 mg/kg, peak plasma concentration of degarelic was reached within 6 hours, at 330 ng/mL. Ki = 0.082 ng/mL, with 93% of receptors completely inhibited; mean residence time (MRT) = 4.5 days. Excretion occurred in feces (70%–80%) and kidneys (20%–30% of the drug was excreted unchanged). Central compartment: 8.88–11.4 L; peripheral compartment: 40.9 L. In patients with prostate cancer, clearance after subcutaneous injection of degarelic was approximately 9 L/hr. Protein binding in mouse, rat, dog, monkey, and human plasma was determined using (3)H-degarelic and ultracentrifugation. Protein binding in animal and human plasma was approximately 90%. The radioactivity distribution of (3)H-degarelk was studied in rats, dogs, and monkeys after administration at doses of 0.03 mg/kg, 0.003 mg/kg, and 0.0082 mg/kg, respectively. Tissue radioactivity was measured after euthanasia and autopsy. High concentrations were primarily observed at the subcutaneous injection site and in excretory organs. Lower drug concentrations, but still higher than plasma concentrations, were typically observed in certain organs of the endocrine and reproductive systems, most of which contain specific receptors for gonadotropin-releasing hormone (LHRH). Higher drug concentrations were also observed in organs rich in reticuloendothelial cells during the elimination phase. No signs of tissue retention were observed. The radioequilibrium following subcutaneous injection of (3)H-degarelk was investigated in rats, dogs, and monkeys. Degarelk is primarily excreted unchanged in the urine and undergoes peptide degradation during elimination via the hepatobiliary pathway in animals and humans. Subcutaneous administration of degarelk creates a local drug reservoir at the injection site, leading to sustained and prolonged release of the active drug. Drug release from the drug reservoir depends on the concentration in the formulation and the volume administered. Furthermore, in repeated-dose studies, increasing the drug concentration in the administered formulation leads to a subproportional increase in peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) within the dosing interval, an increase in trough plasma concentration (Ctrough), and a prolonged terminal half-life (t1/2), thus prolonging the time required to reach steady state, and a tendency for a prolonged time to peak plasma concentration (Tmax). After subcutaneous injection, degarelic forms a drug reservoir at the injection site, from which the drug is slowly released into the bloodstream. Following a single subcutaneous injection of a 240 mg dose (40 mg/mL), peak plasma concentrations of degarelic are typically reached within 2 days. The pharmacokinetic behavior of degarelic is significantly influenced by its concentration in the injection solution. Approximately 90% of the drug is bound to plasma proteins. No quantitatively significant metabolites were detected in plasma after subcutaneous administration. In vitro studies have shown that degarelix is neither a substrate, inducer, nor inhibitor of cytochrome P-450 (CYP) enzymes or the P-glycoprotein transport system. Degarelix elimination is biphasic; in prostate cancer patients, the median terminal half-life after subcutaneous injection of a 240 mg dose (40 mg/mL) is approximately 53 days. Degarelix undergoes peptide hydrolysis during its passage through the hepatobiliary system and is primarily excreted in feces as peptide fragments. Approximately 20-30% of degarelix is excreted by the kidneys after administration, suggesting that approximately 70-80% is excreted via the hepatobiliary system. For more complete data on the absorption, distribution, and excretion of degarelix (6 items in total), please visit the HSDB record page. Metabolites/Metabolites: During its passage through the hepatobiliary system, 70-80% of degarelix undergoes peptide hydrolysis and is then excreted in feces. No active or inactive metabolites are produced, and no CYP450 isoenzymes are involved.
The stability of degarelk was investigated in the liver microsomes of male rats, guinea pigs, rabbits, dogs, monkeys, and humans for up to 60 minutes. No degradation of degarelk was detected in the liver microsomes of rabbits, dogs, monkeys, and humans. A slight trend of degradation of degarelk was observed in the liver microsomes of guinea pigs and rats. Further in vitro metabolism of degarelk was investigated in human liver microsomes for up to 60 minutes. Degarelk has been reported to have a similar metabolic pattern in humans and animals. Degarelk is hardly a substrate for oxidative metabolism, but it is degraded by peptidases to generate various truncated peptides. Low concentrations of only one metabolite were observed in human plasma, and this metabolite was also detected in rats, dogs, and monkeys.
Biological Half-Life
Terminal half-life: 41.5–70.2 days; Absorption half-life: 32.9 hours; Injection site half-life: 1.17 days.
Degarelix is eliminated in a biphasic manner, with a median terminal half-life of approximately 53 days after subcutaneous injection of a 240 mg dose (40 mg/mL) in patients with prostate cancer.

Hepatotoxicity
Degarelix treatment is associated with elevated serum enzymes in up to one-third of patients. However, these elevations are usually mild and self-limiting, resolving spontaneously even without dose adjustment. Less than 1% of patients have ALT values exceeding three times the upper limit of normal. A small number of patients require discontinuation of the drug due to elevated serum enzymes, but no cases of jaundice or clinically significant acute liver injury have been reported in early clinical trials of degarelix. Since its approval and widespread use, despite limitations in the general use of degarelix, no clinically significant cases of liver injury have been reported. Probability Score: E (Unlikely to be the cause of clinically significant liver injury). Protein Binding 90% of the drug is bound to plasma proteins.

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Drug Interactions
Because androgen deprivation therapy may prolong the QTc interval, the safety of degarelix should be carefully evaluated when used in combination with drugs known to prolong the QTc interval or torsades de pointes (e.g., class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs, methadone, cisapride, moxifloxacin, antipsychotics, etc.).

[1]. An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer. Onco Targets Ther. 2013 Apr 16;6:391-402.

[2]. In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonistdegarelix on human prostate cell growth. PLoS One. 2015 Mar 26;10(3):e0120670.

[3]. Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormoneantagonist: degarelix. J Pharmacol Exp Ther. 2002 Apr;301(1):95-102.

[4]. Metabolite profiles of degarelix, a new gonadotropin-releasing hormone receptor antagonist, in rat, dog, and monkey. Drug Metab Dispos. 2011 Oct;39(10):1895-903.

Therapeutic Uses

Degarelix is used to treat advanced prostate cancer. /See US product label for usage details/
Drug Warnings
Degarelix is contraindicated in pregnant women or women who may become pregnant. Use of degarelix in pregnant women may cause harm to the fetus.
FDA Pregnancy Risk Class: X / Contraindicated during pregnancy. Animal or human studies, or investigational or post-marketing reports, have demonstrated that the fetal abnormalities or risks significantly outweigh any potential benefit to the patient. /
The most common adverse reactions at the injection site are pain (28%), erythema (17%), swelling (6%), induration (4%), and nodules (3%). These adverse reactions are mostly transient, mild to moderate in severity, occur primarily at the initial dose, and lead to discontinuation in a very low percentage (<1%). The incidence of grade 3 injection site reactions is ≤2% in patients receiving degarelix treatment. A total of 1325 patients with prostate cancer received Firmagon treatment, administered monthly (60-160 mg) or as a single dose (up to 320 mg). Of these, 1032 patients (78%) received treatment for at least 6 months, and 853 patients (64%) received treatment for one year or longer. The most common adverse reactions during Firmagon treatment included injection site reactions (such as pain, erythema, swelling, or induration), hot flashes, weight gain, fatigue, and elevated serum transaminase and gamma-glutamyl transferase (GGT) levels. Most adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reactions occurring in less than 1% of cases. For more complete (15) drug warnings for Degarelix, please visit the HSDB record page. Pharmacodynamics: Degarelix is a synthetic derivative of the GnRH decapeptide and a ligand for the GnRH receptor. Endogenous GnRH binds to its receptors, triggering the production of gonadotropins and androgens. Degarelix antagonizes GnRH receptors, thereby blocking the pituitary release of LH and FSH. LH and FSH levels decrease in a concentration-dependent manner. This reduction in LH leads to decreased testosterone release from the testes.

C₈₂H₁₀₃CLN₁₈O₁₆

1632.26

1630.748

C, 60.34; H, 6.36; Cl, 2.17; N, 15.45; O, 15.68

214766-78-6

Degarelix-d7; Degarelix acetate hydrate; 934246-14-7;214766-78-6;Degarelix-d7;934016-19-0

16136245

Ac-D-2Nal-D-Phe(4-Cl)-D-3Pal-Ser-Phe(4-S-dihydroorotamido)-D-Phe(4-ureido)-Leu-Lys(iPr)-Pro-D-Ala-NH2

XXXSXXLXPA

White to off-white solid powder

1.3±0.1 g/cm3

1.620

4.45

17

18

41

117

3390

11

C[C@H](C(N)=O)NC([C@H]1N(C([C@H](CCCCNC(C)C)NC([C@H](CC(C)C)NC([C@@H](CC2=CC=C(NC(N)=O)C=C2)NC([C@H](CC3=CC=C(NC([C@H](CC(N4)=O)NC4=O)=O)C=C3)NC([C@H](CO)NC([C@@H](CC5=CC=CN=C5)NC([C@@H](CC6=CC=C(Cl)C=C6)NC([C@@H](CC7=CC=C8C=CC=CC8=C7)NC(C)=O)=O)=O)=O)=O)=O)=O)=O)=O)CCC1)=O

MEUCPCLKGZSHTA-XYAYPHGZSA-N

InChI=1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66+,67+,68+/m1/s1

(4S)-N-[4-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2R)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-6-(propan-2-ylamino)hexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[4-(carbamoylamino)phenyl]-1-oxopropan-2-yl]amino]-3-oxopropyl]phenyl]-2,6-dioxo-1,3-diazinane-4-carboxamide

Degarelix Free Base; HSDB 7817; HSDB7817; HSDB-7817

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~10 mg/mL (~6.1 mM)
H2O: ~5 mg/mL (~3.1 mM)

Solubility in Formulation 1: ≥ 1 mg/mL (0.61 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (0.61 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 10.0 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: ≥ 1 mg/mL (0.61 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 10.0 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.)