Degarelix

Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer.[3][4]

Degarelix

Clinical data
Trade names	Firmagon, others
Other names	FE-200486
AHFS/Drugs.com	Monograph
MedlinePlus	a609022
License data	EU EMA: by INN US DailyMed: Degarelix US FDA: Degarelix
Pregnancy category	AU: D [1] US: X (Contraindicated) [1] Contraindicated[1]
Routes of administration	Subcutaneous injection
Drug class	GnRH analogue; GnRH antagonist; Antigonadotropin
ATC code	L02BX02 (WHO)
Legal status
Legal status	UK: POM (Prescription only) [2] US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	30–40%
Protein binding	~90%
Metabolism	Subject to common peptidic degradation during passage through the hepato-biliary system; not a substrate for the human CYP450 system
Elimination half-life	23–61 days
Excretion	Feces: 70–80% Urine: 20–30%
Identifiers
CAS Number	214766-78-6^Y
PubChem CID	16136245
IUPHAR/BPS	5585
DrugBank	DB06699^N
ChemSpider	17292756^N
UNII	SX0XJI3A11
KEGG	D08901^Y
ChEMBL	ChEMBL264089^N
ECHA InfoCard	100.234.843
Chemical and physical data
Formula	C82H103ClN18O16
Molar mass	1632.29 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C[C@H](C(=O)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccc(cc2)NC(=O)N)NC(=O)[C@H](Cc3ccc(cc3)NC(=O)[C@@H]4CC(=O)NC(=O)N4)NC(=O)[C@H](CO)NC(=O)[C@@H](Cc5cccnc5)NC(=O)[C@@H](Cc6ccc(cc6)Cl)NC(=O)[C@@H](Cc7ccc8ccccc8c7)NC(=O)C
InChI 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^N Key:MEUCPCLKGZSHTA-XYAYPHGZSA-N^N
^NY (what is this?)  (verify)

Testosterone is a male hormone that promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castration) levels is often the treatment goal in the management of advanced prostate cancer. Degarelix has an immediate onset of action, binding to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocking their interaction with GnRH. This induces a fast and profound reduction in luteinizing hormone (LH), follicle-stimulating hormone (FSH) and in turn, testosterone suppression.[5]

Medical uses

The GnRH antagonist degarelix, through its ability to reduce serum testosterone, is used to treat hormone-sensitive prostate cancer.[6]

Side effects

As with all hormonal therapies, degarelix is commonly associated with hormonal side effects such as hot flashes and weight gain.[6][7][8] Due to its mode of administration (subcutaneous injection), degarelix is also associated with injection-site reactions such as injection-site pain, erythema or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter.[6] Less common: Anemia. Diarrhea, nausea. Hyperhidrosis including night sweats, rash. Gynecomastia, testicular atrophy, erectile dysfunction. Increased transaminases. Musculoskeletal pain and discomfort. Dizziness, headache. Insomnia. Weight gain. Chills, fever, fatigue, flu-like illness.[9]

Pharmacology

GnRH antagonists (receptor blockers) such as degarelix are synthetic peptide derivatives of the natural GnRH decapeptide – a hormone that is made by neurons in the hypothalamus. GnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible binding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patient's blood. Measuring PSA levels helps to monitor how patients with prostate cancer are responding to treatment.

Unlike GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare.[10] Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as bone pain, urethral obstruction, and spinal cord compression. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.

GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer where fast control of disease is needed.

History

In December 2008, the US Food and Drug Administration (FDA) approved degarelix for the treatment of patients with advanced prostate cancer in the United States.[11] It was subsequently approved by the European Commission at the recommendation of the European Medicines Agency (EMA) in February 2009 for use in adult male patients with advanced, hormone-dependent prostate cancer.[12] Ferring Pharmaceuticals markets the drug under the name Firmagon.[12]

Research

Degarelix is studied for use as a chemical castration agent on sex offenders in Sweden.[13] A study published on April 29, 2020 in JAMA Psychiatry demonstrated a reduced the risk score for committing child sexual abuse in men with pedophilic disorder 2 weeks after initial injection.[14]

See also

• Gonadotropin-releasing hormone receptor § Antagonists

References

1. "Degarelix (Firmagon) Use During Pregnancy". Drugs.com. 3 February 2020. Retrieved 25 February 2020.
2. "Firmagon 120mg Injection - Summary of Product Characteristics (SmPC)". (emc). 15 January 2020. Retrieved 25 February 2020.
3. "Firmagon- degarelix kit". DailyMed. 18 September 2019. Retrieved 26 February 2020.
4. "Degarelix Acetate Monograph for Professionals". Drugs.com. 7 October 2019. Retrieved 25 February 2020.
5. Princivalle M, Broqua P, White R, Meyer J, Mayer G, Elliott L, et al. (March 2007). "Rapid suppression of plasma testosterone levels and tumor growth in the dunning rat model treated with degarelix, a new gonadotropin-releasing hormone antagonist". The Journal of Pharmacology and Experimental Therapeutics. 320 (3): 1113–8. doi:10.1124/jpet.106.112326. PMID 17179469.
6. Clinton TN, Woldu SL, Raj GV (June 2017). "Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer". Expert Opinion on Pharmacotherapy. 18 (8): 825–832. doi:10.1080/14656566.2017.1328056. PMC 7171911. PMID 28480768.
7. Gittelman M, Pommerville PJ, Persson BE, Jensen JK, Olesen TK (November 2008). "A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America". The Journal of Urology. 180 (5): 1986–92. doi:10.1016/j.juro.2008.07.033. PMID 18801505.
8. Van Poppel H, Tombal B, de la Rosette JJ, Persson BE, Jensen JK, Kold Olesen T (October 2008). "Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer". European Urology. 54 (4): 805–13. doi:10.1016/j.eururo.2008.04.065. PMID 18538469.
9. "Firmagon "Ferring Pharmaceuticals A/S" - Felleskatalogen". www.felleskatalogen.no. Retrieved 5 May 2020.
10. van Poppel H, Nilsson S (June 2008). "Testosterone surge: rationale for gonadotropin-releasing hormone blockers?". Urology. 71 (6): 1001–6. doi:10.1016/j.urology.2007.12.070. PMID 18407326.
11. "FDA Approves Ferring Pharmaceuticals' Degarelix (Generic Name) for Treatment of Advanced Prostate Cancer" (Press release). Ferring Pharmaceuticals. 24 December 2008. Archived from the original on 8 June 2011. Retrieved 25 February 2020 – via PR Newswire.
12. "Firmagon EPAR". European Medicines Agency (EMA). 10 January 2020. Retrieved 25 February 2020.
13. "Pedofiler ska stoppas – med kemisk kastrering". Expressen.
14. Landgren V, Malki K, Bottai M, Arver S, Rahm C (April 2020). "Effect of Gonadotropin-Releasing Hormone Antagonist on Risk of Committing Child Sexual Abuse in Men With Pedophilic Disorder: A Randomized Clinical Trial". JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.0440. PMC 7191435. PMID 32347899.

External links

• "Degarelix". Drug Information Portal. U.S. National Library of Medicine.