Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Hormonal Anticancer Drugs:

  • Gonadotropin-releasing hormone (GnRH) antagonists:

    • Overview:

      • Four synthetic decapeptides had been used clinically, functioning as GnRH receptor competitive blockers.⁵

        • These include:

          • Ganirelix (Antagon)

          • Cetrorelix (Cetrotide)

          • Abarelix (Plenaxis) *Removed from U.S. market (2005; side-effects¹⁰; limited efficacy relative to agonists⁷;may still be marketed in the Netherlands and Germany¹⁰ )

          • Degarelix (Firmagon).⁵ 

        • These agents inhibit FSH and LH secretion (dose-dependent)

          • Ganirelix and cetrorelix are used in connection with controlled ovarian stimulation procedures.

          • Degarelix and abarelix had been approved for treatment of advanced prostate cancer.¹¹ 

            • However, abarelix was withdrawn from the U.S. market in 2005 due to side effects ("local reactions and anaphylaxis"².)

      • Degarelix (Firmagon)⁸

        • Overview:

          • Degarelix is classified as a GnRH antagonist.⁸  

            • Degarelix competitively inhibits the action of GnRH on the pituitary.

            • As a consequence, release of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is prevented.

            • These interactions lead to rapid suppression of testicular testosterone production.

            • Degarelix is an FDA approved medication for treating advanced, metastatic prostate cancer.¹¹

              •  

                Degarelix (Firmagon)

        • Absortion, Distribution, Biotransformation, Excretion:

          • Degarelix is administered as a depot gel with the drug released biphasically exhibiting a median plasma t_1/2 of about 42 days (starting dose) and 28 days (maintenance dose).^11,1

            • Absorption:  Usually most men (96%) achieve, following degarelix administration, castration level reduction in serum testosterone within about three days following initial dosing (loading-dose, 240 mg degarelix administered as subcutaneous injections of 120 mg).

              • After two weeks following dosing, about 99% of men achieve castration level.¹³

            • Distribution:  Degarelix distributes in total body water (V_d >1000 L) and exhibits an in vitro level of plasma protein binding of >90%.¹³

            • Biotransformation (Metabolism):

              • About 20%-30% of administered degarelix is excreted by the kidneys.

                • Hepatobiliary excretion accounts for the remaining 70%-80% of excreted drug.

                  • In the hepatobiliary system, degarelix undergoes peptide hydrolysis accounting for significant excretion as peptide fragments (in feces).¹³

        • Mechanism of Action:

          • Degarelix is a competitive antagonist relative to endogenous GnRH on GnRH receptor binding (on pituitary gonatotroph cells).

            • This action results in Leutinizing-Hormone (LH) direct suppression and in turn significant decline in testosterone production, sufficient to cause "chemical castration a.k.a. "medical castration."

              • Given that degarelix is a competitive antagonist, as opposed to an agonist, pituitary LH levels do not rise and there is no increase in testicular androgen levels, an effect seen with the GnRH agonists.

                • As a result no clinical flare is observed.¹³

        • Clinical Uses:

          • Degarelix is used in treating prostate cancer.¹¹  

            • Degarelix acetate has been approved by the FDA for treating advanced, metastatic prostate malignancies.

              • Degarelix administration results in reduction of testosterone levels to 50 ng/dL or less.

                • This degree of suppression is described as "medical castration."

                  • Following degarelix use, PSA (prostate-specific antigen) levels are reduced more quickly than that observed following GnRH agonists and this reduction occurs without a testosterone surge.¹¹  

            • Comparison of the decline in serum testosterone following degarelix vs. leuprolide treatment is shown below.⁸

               

              • Testosterone Level Decline:  Degarelix vs. Leuprolide⁹

                Attribution:  Shore ND Experience with degarelix in the treatment of prostate cancer Ther Adv Urol 5(1):  11-24, Feb 2013. The figure above is "Figure 1" (reference 9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547532/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547532/pdf/10.1177_1756287212461048.pdf

        • Adverse Effects/Toxicities:

          • The primary, common adverse effect associated with degarelix administration is injection site reactions (pain and erythema) which occur more commonly with degarelix compared to leuprolide.

            • Other adverse effects appear similar to those is associated with leuprolide administration. ¹³

              • Numerous side effects associated with leuprolide administration have been reported (side effects similar to goserelin).

                • Some of these include:

                  • Hot flashes

                  • Impotence

                  • Reduced frequency of erections.

                • Since this agent may be used to treat prostate cancer symptoms as well as, in women, breast cancer or endometriosis a broad range of gender-dependent side effects may be expected.⁹