Gonadotrophin-releasing hormone (GnRH) receptor . [1][2][3]

Abarelix causes a marked increase in histamine release at 30 and 300 µg/mL[1]. The first GnRH antagonist to be created,arelix has a very low short-term complication rate and can quickly and consistently lower testosterone levels to castrate levels without the need for co-administration of an antiandrogen[2]. Abarelix shows to quickly and significantly lower follicle-stimulating hormone levels to levels below those of an LHRH agonist. Abarelix causes medical castration more quickly and does not raise serum testosterone levels, which can worsen a patient's condition or trigger a flare phenomenon. This is especially dangerous for patients with symptomatic, metastatic diseases.

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In an ex vivo model of human skin samples, the histamine-releasing potential of abarelix was tested. Human skin samples were incubated with abarelix at concentrations of 3, 30, or 300 µg/ml. Abarelix caused a significant increase in histamine release at 30 and 300 µg/ml (143 ± 29% and 362 ± 58%, respectively, P < 0.05) compared to basal release. [3]

In a Phase II open-label study, patients with prostate cancer received a 100-mg abarelix 1-month depot intramuscularly on days 1 and 15, followed by 50 mg intramuscularly at 28-day intervals. Castration (testosterone < 50 ng/mL) was achieved in 34.5% of patients at day 2, increasing to 82.3% at day 13. None of the patients treated with abarelix reported testosterone flare. [1]
In an open-label study of abarelix in patients with advanced symptomatic prostate cancer, 81 patients received abarelix 100 mg per month for 6 months. Testosterone reduction was rapid, with 79% of patients achieving castrate levels at day 8, and 97% and 93% being at castrate levels at days 85 and 169, respectively. PSA level decreased by 75% at day 15. 90% (65/72) of men had an improvement in pain score and/or analgesic use. Of seven patients at risk of impending neurological compromise, none developed spinal cord compression. At day 85, 21 of 34 patients had improvements in bladder neck outlet obstruction, and 10 of 13 catheterized patients no longer required catheters. [1]
In a Phase III open-label study (Study 149-98-02), patients (n=180) received abarelix 100 mg (with an additional dose at day 15) monthly for 1 year. Medical castration was achieved more rapidly with abarelix (24% by day 2, 72% by day 8; vs none in leuprolide group; P < 0.001). No abarelix-treated patient experienced a testosterone surge, compared to 80% in the leuprolide group (P < 0.001). Overall, 91.7% of abarelix patients achieved castrate levels. [2]
In the ABACAS 1 study (Phase III), 177 patients with advanced or metastatic cancer were treated for 12 months with abarelix 100 mg 4-weekly. Median time to castration was significantly shorter for abarelix than for goserelin plus bicalutamide (7 vs 21 days; P < 0.001). Castration rates on day 3 were significantly higher for abarelix (36% vs 0%; P < 0.001). Flare was not reported in any abarelix-treated patients, in comparison with 96% of men receiving goserelin plus bicalutamide (P < 0.001). PSA values were significantly lower on day 7 in abarelix-treated patients (P = 0.047). [1]
In an open-label study (149-98-04) of abarelix in 81 symptomatic prostate cancer patients at risk of bilateral orchiectomy, the primary endpoint (avoidance of bilateral orchiectomy for at least 12 weeks of treatment) was met. None of the eight patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms. Ten of 13 patients with bladder outlet obstruction and a bladder drainage catheter had the catheter removed by 12 weeks. Eleven of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic analgesia at 12 weeks. [2]

Absorption, Distribution and Excretion
Following intramuscular injection of 100 mg abarig, absorption is slow, reaching an average peak concentration of 43.4 ng/mL approximately 3 days post-injection. Metabolism/Metabolites In vitro hepatocyte (rat, monkey, human) and in vivo (rat and monkey) studies indicate that the major metabolites of abarig are formed via peptide bond hydrolysis. No significant oxidized or conjugated metabolites of abarig were found in vitro or in vivo. There is no evidence that cytochrome P-450 is involved in the metabolism of abarig. Biological Half-Life 13.2 ± 3.2 days

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Following intramuscular administration of abarelix depot (100 mg), the drug is absorbed slowly with a mean peak concentration (Cmax) of 43.3 ng/ml observed approximately 3 days (tmax) after the injection. The mean elimination half-life (T1/2) for the depot formulation was 13.2 days. The apparent volume of distribution during the terminal phase (V2/F) was 4040 ± 1607 L, implying extensive distribution. [2]
In vitro hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys demonstrated that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites were found. There is no evidence of cytochrome P450 involvement in the metabolism of abarelix. [2]
In humans, approximately 13% of unchanged abarelix was recovered in urine after a 15 µg/kg intramuscular injection; there were no detectable metabolites in urine. Renal clearance of the drug was 14.4 L/day (or 10 ml/min) after administration of abarelix 100 mg. [2]
After a single intramuscular injection of abarelix injectable solution (15 µg/kg), the Cmax was 57.8 ± 15.3 ng/ml, tmax was 1.0 ± 0.3 hours, and T1/2 was 0.22 ± 0.08 days. The relative bioavailability (Fr) of the depot formulation compared to the solution was 0.52 ± 0.11. [2]

Protein Binding
96-99%

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In Phase III clinical trials, abarelix demonstrated an overall similar safety profile compared to LHRH agonist monotherapy and a superior safety profile compared to LHRH agonist plus antiandrogen combination therapy. The most common treatment-related adverse events (occurring in ≥2% of abarelix patients through 1 year) included fatigue (14%), headache (9%), testis disorder/atrophy (6%), pain (5%), micturition frequency (5%), dizziness (3%), pruritus (3%), diarrhea (3%), paresthesia (3%), myalgia (2%), nocturia (2%), rash (2%), and testicular pain (2%). [2]
Overall, there was a greater incidence of immediate-onset systemic allergic reactions in abarelix-treated groups compared with control arms. In all studies, 15 of 1397 (1.1%) patients experienced either urticaria or transient pruritus (n=8) or transient lowering of blood pressure or fainting (n=7; representing 0.5% of all patients treated). [2]
In a Phase III study, hypersensitivity occurred at approximately 1%, a rate only marginally higher than that seen with leuprolide. No anti-abarelix antibodies were detected in men treated with abarelix. [1]
In the ABACAS 1 study, the overall incidence of spontaneously reported adverse events was similar across treatment groups (86% in abarelix group). Treatment-related adverse events occurring in ≥3% of the abarelix group included asthenia (10%), pruritus (7%), neoplasm malignant aggravated (6%), pain (3%), gynaecomastia (5%), hepatic enzymes increased (5%), weight increase (5%), back pain (3%), headache (3%), fatigue (3%), myalgia (3%), skeletal pain (3%), skin dry (3%). [2]
In an ex vivo human skin model, abarelix caused significant histamine release at 30 and 300 µg/ml concentrations (143 ± 29% and 362 ± 58% increase, respectively, P < 0.05), indicating a higher histamine-releasing capacity compared to degarelix. [3]

[1]. A novel GnRH antagonist, causes minimal histamine release compared with abarelix in an ex vivo model of human skin samples. Br J Clin Pharmacol. 2010 Oct;70(4):580-7.

[2]. Abarelix and other gonadotrophin-releasing hormone antagonists in prostate cancer. BJU Int. 2009 Dec;104(11):1580-4.

[3]. Abarelix for injectable suspension: first-in-class releasing hormone antagonist for prostate cancer. Future Oncol. 2006 Dec;2(6):677-96.

Abarelix is a polypeptide compound composed of ten naturally occurring and non-natural amino acid residues arranged linearly. It is a hormone antagonist and anti-tumor drug. It is a synthetic decapeptide and an antagonist of gonadotropin-releasing hormone (GnRH). This drug was marketed by Praecis Pharmaceuticals under the brand name Plenaxis. Praecis announced its voluntary withdrawal of the drug from the market in June 2006. Abarelix is a synthetic decapeptide and an antagonist of naturally occurring gonadotropin-releasing hormone (GnRH). Abarelix directly and competitively binds to and blocks the gonadotropin-releasing hormone receptor in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, inhibition of LH secretion prevents the release of testosterone. Therefore, since testosterone is essential for maintaining prostate growth, this may help alleviate symptoms associated with benign prostatic hyperplasia (BPH) or prostate cancer. Drug Indications: Palliative treatment of advanced prostate cancer.
FDA Label

Mechanism of Action

Abalix binds to the gonadotropin-releasing hormone receptor and acts as a potent inhibitor of gonadotropin secretion.
Pharmacodynamics

Used for palliative treatment of advanced prostate cancer. Abalix is a luteinizing hormone agonist that inhibits testicular or follicle-stimulating steroid production.

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Abarelix is a pure GnRH antagonist (first-in-class) that binds immediately and competitively to GnRH receptors in the pituitary gland, causing rapid, reversible decreases in LH, FSH, and testosterone without inducing a testosterone surge (flare). [2]
Abarelix was the first GnRH antagonist approved by the US FDA in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma when rapid androgen suppression is necessary. It is also approved in Germany. In the USA, physicians are required to register with a user-safety programme to prescribe the drug. [1]
Unlike LHRH agonists, abarelix does not cause a testosterone surge or clinical flare, which can be particularly dangerous for patients with metastatic, symptomatic disease. It produces medical castration more quickly. [2]
Abarelix has been shown to promptly and substantially reduce follicle-stimulating hormone (FSH) levels to lower than LHRH agonist. [2]
In a study of patients with hormone-refractory (androgen-independent) prostate cancer progressing after orchiectomy, treatment with abarelix resulted in marked reduction in circulating FSH, but no patients met the criteria for a confirmed 50% reduction in PSA. [2]

C72H95CLN14O14

1416.06

1414.684

C, 61.07; H, 6.76; Cl, 2.50; N, 13.85; O, 15.82

183552-38-7

183552-38-7; 785804-17-3 (acetate)

16131215

White to off-white solid powder

1.3±0.1 g/cm3

1688.4±65.0 °C at 760 mmHg

974.9±34.3 °C

0.0±0.3 mmHg at 25°C

1.601

5.18

13

16

38

101

2770

10

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](CC(N)=O)NC([C@H](CC2=CC=C(C=C2)O)N(C([C@H](CO)NC([C@@H](CC3=CC=CN=C3)NC([C@@H](CC4=CC=C(Cl)C=C4)NC([C@@H](CC5=CC=C6C=CC=CC6=C5)NC(C)=O)=O)=O)=O)=O)C)=O)=O)=O)=O)CCC1)=O

AIWRTTMUVOZGPW-HSPKUQOVSA-N

InChI=1S/C72H95ClN14O14/c1-41(2)32-54(64(93)80-53(17-10-11-30-77-42(3)4)72(101)87-31-13-18-60(87)69(98)78-43(5)63(75)92)81-68(97)58(38-62(74)91)84-70(99)61(37-46-22-27-52(90)28-23-46)86(7)71(100)59(40-88)85-67(96)57(36-48-14-12-29-76-39-48)83-66(95)56(34-45-20-25-51(73)26-21-45)82-65(94)55(79-44(6)89)35-47-19-24-49-15-8-9-16-50(49)33-47/h8-9,12,14-16,19-29,33,39,41-43,53-61,77,88,90H,10-11,13,17-18,30-32,34-38,40H2,1-7H3,(H2,74,91)(H2,75,92)(H,78,98)(H,79,89)(H,80,93)(H,81,97)(H,82,94)(H,83,95)(H,84,99)(H,85,96)/t43-,53+,54+,55-,56-,57-,58-,59+,60+,61+/m1/s1

(2R)-2-[[(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]-methylamino]-3-(4-hydroxyphenyl)propanoyl]amino]-N-[(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]butanediamide

PPI-149; PPI 149; PPI149; R-3827; R3827; R 3827; Abarelix; Abarelix acetate. Brand name: Plenaxis

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: ≥ 14.2 mg/mL (~10.0 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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