Relugolix is the first and currently only Orally-Administered GnRH Receptor Antagonist Approved for the treatment of Prostate Cancer: A Review

 

Mr. Sunil R Bavaskar, Mr. Mayur R. Bhurat

Shri. Prakashchand Jain College of Pharmacy and Research, Palaskhede, Jamner Maharashtra India.

*Corresponding Author E-mail: bavaskarsunilkumar@gmail.com

 

ABSTRACT:

Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist used in the treatment of several hormone-responsive conditions. It was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis. Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer-similar therapies such as degarelix require subcutaneous administration-and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals.In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer1,2

 

KEYWORDS: Relugolix, gonadotropin-releasing hormone (GnRH) receptor, prostate cancer.

 

 


INTRODUCTION:

Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist used in the treatment of several hormone-responsive conditions. It was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis.

 

Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer - similar therapies such as degarelix require subcutaneous administration-and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals. In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer.

 

Relugolix, sold under the brand names Orgovyx and Relumina, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in womenIt is also under development for use in the treatment of endometriosis It is taken by mouth once per day.1,2,3

Side effects of relugolix include menstrual abnormalities, hot flashes, excessive sweating, headache, and decreased bone mineral density. Relugolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor. Unlike most other GnRH modulators, but similarly to elagolix (brand name Orilissa.As of February 2019, relugolix is in phase III clinical trials for endometriosis. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020.

 

Relugolix was first described in 2004. It superseded sufugolix (developmental code name TAK-013), which was developed by the same researchers. Relugolix was approved for the treatment of uterine fibroids in Japan on 8 January 2019. It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (brand name Orilissa) in July 2018. Relugolix was approved for the treatment of prostate cancer in the United States on 18 December 2020.

 

The FDA approved relugolix based on evidence from a clinical trial (NCT03085095) of 930 participants 48 to 97 years old with advanced prostate cancer. The trial was conducted at 155 sites in the United States, Canada, and countries in South America, Europe and the Asia Pacific region. All participants in the trial had advanced prostate cancer. Participants were randomly assigned to receive either one relugolix tablet daily (on the first day they received three tables) or an active control (leuprolide acetate) which was given as an injection under the skin every three months. The participants and healthcare providers were aware of which treatment was being given. The treatment lasted for 48 weeks. The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained low testosterone level equal to castration.3,4

 

Structure

 

IUPAC Name

1-(4-{1-[(2,6-difluorophenyl) methyl]-5-[(dimethylamino) methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1H,2H,3H,4H-thieno[2,3-d] pyrimidin-6-yl} phenyl)-3-methoxyurea.

Indication:

Relugolix is indicated for the treatment of adult patients with advanced prostate cancer

 

Pharmacodynamics:

Approximately 56% of patients achieved castrate-level testosterone concentrations (<50 ng/dL) by day 4 of therapy and 97% of patients maintain these levels through 48 weeks of therapy. Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations.

 

Androgen deprivation therapies may prolong the QTc interval and should therefore be used with caution in patients having a high baseline risk of QTc prolongation, such as those with electrolyte abnormalities, congestive heart failure, or using other medications known to prolong the QTc interval. Based on its mechanism of action and data from animal studies, relugolix may result in fetal harm if administered to pregnant females - male patients with female partners should be advised to use effective contraception throughout therapy and for 2 weeks following cessation of therapy to prevent inadvertent fetal exposure.1,2,3

 

Mechanism of action:

The pathogenesis and progression of prostate cancer appear driven, at least in part, by the effects of testosterone. Androgen deprivation has been demonstrated to result in cell death and tumor regression in many well-differentiated prostate cancer cell lines - for this reason, androgen deprivation therapy (ADT) has become a standard in the treatment of prostate cancer, particularly in advanced disease.

 

Testosterone production in males is carried out in the Leydig cells of testes and is stimulated by luteinizing hormone (LH), which itself is produced in the pituitary gland following the binding of gonadotropin-releasing hormone (GnRH) to corresponding GnRH receptors. Relugolix is a competitive antagonist of these GnRH receptors, thereby decreasing the release of LH and, ultimately, testosterone.

 

Absorption:

The Cmax and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the Cmax increases greater than proportionally to the dose. Following the administration of 120mg once daily, the steady-state AUC and Cmax of relugolix were 407 (±168) ng.hr/mL and 70 (± 65) ng/mL, respectively.

 

The absolute oral bioavailability of relugolix is approximately 12% and the median Tmax following oral administration is 2.25 hours4,5

Protein binding:

Relugolix is 68-71% protein-bound in plasma, primarily to albumin and, to a lesser extent, α1-acid glycoprotein

 

Metabolism:

Relugolix is metabolized mainly by the CYP3A subfamily of P450 enzymes, with a smaller contribution by CYP2C8

 

Route of elimination:

Approximately 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained unchanged.

 

Half life:

The average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours

 

Uses:

Relugolix is approved in the United States for the treatment of prostate cancer in men and in Japan for the treatment of uterine fibroids (uterine leiomyoma) in women. It is used at a dosage of 120 mg once daily by mouth in the treatment of prostate cancer (after a single 360 mg loading dose on the first day of therapy) and at a dosage of 40 mg once daily in the treatment of uterine fibroid.5,6

 

Side effects:

The main side effects of relugolix for uterine fibroids include abnormal uterine bleeding (24.6–48.6% vs. 6.3% for placebo), hot flashes (42.8–45.5% vs. 0% for placebo), heavy menstrual bleeding (12.1–49.3% vs. 9.4% for placebo), headache (12.3–15.2%), and excessive sweating (9.4–15.2% vs. 0% for placebo). In addition, decreased bone mineral density occurs with relugolix (21.7% decrease by week 12, 24.4% decrease by week 24).

 

Chemical And Physical Properties

Property Name

Property Value

Molecular Weight

623.6 g/mol

XLogP3-AA

3.2

Hydrogen Bond Donor Count

2

Hydrogen Bond Acceptor Count

11

Rotatable Bond Count

9

Exact Mass

623.176245 g/mol

Monoisotopic Mass

623.176245 g/mol

Topological Polar Surface Area

158 Ų

Heavy Atom Count

44

Formal Charge

0

 

Synthesis.

 


CONCLUSION:

Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist used in the treatment of several hormone-responsive conditions. It was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis.

 

Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer-similar therapies such as degarelix require subcutaneous administration-and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals. In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer.

 

ACKNOWLEDGEMENT:

We are very thankful to Secretary Shri.Manojkumarji Kawadiya for providing us facility and support completion of this work.

 

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Received on 13.03.2021         Modified on 28.05.2021

Accepted on 13.07.2021   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2021; 11(4):247-250.

DOI: 10.52711/2231-5691.2021.00043