Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Hormonal Anticancer Drugs: 

  • Luteinizing hormone releasing hormone agonist (LHRH):

    • Overview:⁶  

      • In 1941 experiments demonstrated that reducing serum testosterone (by castration or estrogen treatment) induced regression of metastatic prostate cancer.⁶  

        • Such approaches were designated as Androgen Deprivation Therapy (ADT).

          • ADT continues to be an element in prostate cancer therapy.

          • Occasionally, testicular surgery (bilateral orchiectomy) is performed to prevent testosterone treatment.

            • Psychological as well as physical adverse effects follow from bilateral orchiectomy which does retard disease advancement.

      • Chemical castration which results in androgen deprivation represents the principal current therapeutic approach used to reduce serum testosterone to a level at least < 50 ng/dL (or <20 ng/dl).⁶  

        • Currently ADT involves using GnRH analogs (Gonadotropin Receptor Hormone) which exhibit greater potency compared to natural GnRH.

          •  

            GnRH Antagonists Versus GnRH Agonists⁸

            Attribution: Slovin SF GnRH Agonists vs. GnRH Agonists  https://www.youtube.com/watch?v=G0rWmEMhmzY (4/2019) OncLiveTV Youtube Channel:   https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

             

      • Clinical Uses:

        • These agents are used in treating prostate cancer and breast cancer.

        • These analogs bind to GnRH receptors (GnRH-R) in the pituitary resulting in an initial increase in Lutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) and testosterone.

          •  LH increases testosterone production by Leydig cells (testicular interstitial cells).

            • FSH increases testicular growth and production of androgen-binding protein by Sertoli cells required for supporting sperm cell maturation.

            • This initial "androgen surge" is associated with the first 3-7 days of treatment.

              • The initial increase (surge) in agonist activity associated with GnRH analog administration may result in a "flare" response due to elevated androgen levels.⁶.

                • This clinical flare may be associated with:

                  • Elevated prostate volume

                  • Spinal cord compression and

                  • Bone pain.

                    • Although no longer common practice, antiandrogen administration has been used to block flare symptoms.

                      • Eamples of antiandrogens used for this purpose include flutamide or bicalutamide.^6,3

            • However, the continuous activation of GnRH receptors causes gonatotroph cellular desensitization as well as reduced GnRH-R expression.

            • This response causes a reduction in Leutinizing-Hormone (LH) synthesis, thus halting testicular steroidogenesis.

              • In summary, gonadal androgen synthesis is suppressed due to feedback inhibition of the Hypothalamic-Pituitary-Gonadal axis.⁶

                •  

                  "Hypothalamus-Hypophysis_Testicle_Hormone-Axis"

                  Attribution:  User: Uwe Gille / CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/) Wikipedia:  https://commons.wikimedia.org/wiki/File:Hypothalamus-Hypophysis-Testicle-Hormone-Axis_(engl.).svg

                •  

                  Hypothalamic-Pituitary_Gonadal Axis

                  Attribution:  Artoria2e5 / CC BY (https://creativecommons.org/licenses/by/3.0) Wikipedia:  https://commons.wikimedia.org/wiki/File:Hypothalamic–pituitary–gonadal_axis.svg

     

    • The analogs, goserelin and leuprolide are given at monthly intervals, as intramuscular depot preparations.

      • This route of administration is considered preferable since parenteral administration results in rapid clearance of the analogs.³

    • Goserelin (Zoladex and others, GOE se rel in))

      • Overview:

        • GnRH synthetic agonists [goserelin, Zoladex; triptorelin, Trelstar; leuprolide, Lupron], are used in treating prostate cancer.⁶

          • In that clinical setting, these agents are administered at high-dose as constant release formulation.

          • Depot formulations for goserelin (as well as for the other approved GnRH agonists) allow for durations of action extending from 1 to 6 months.⁶

    • • Absorption, Distribution, Biotransformaion, Excretion:²

        • GnRH synthetic agonists [goserelin, Zoladex; triptorelin, Trelstar; leuprolide, Lupron], are used in treating prostate cancer.

          • In that clinical setting, these agents are administered at high-dose as constant release formulations.

          • As shown above, GnRH agonists or peptides, similar in structure to the naturally occurring hormone GnRH.

            • Goserelin exhibits a modification with respect to the naturally occurring GnRH in that a d-serine is altered with a t-butyl group. See above:

              • Depot formulations for goserelin (as well as for the other approved GnRH agonists) allow for durations of action extending from 1 to 6 months.

                • Goserelin administration (3.6 mg, depot route of administration) results in an early, short-duration goserelin peak (about 8 hours following administration).

                  • A more prolonged peak is noted about two weeks following administration.

                  • Different serum profiles are associated with the amount of depot drug.

                    • For example, a 10.8 mg depot administration is associated with a decrease in plasma level with a small secondary peak at five weeks.²

        •  Metabolism involves hepatic hydrolysis.²

        •  Elimination of goserelin is mainly by renal excretion with over 90% of the agent found in the urine.

          • Most of the drug is excreted rapidly with about 75% excreted during the first 12 hours.

          •  In the urine, about 20% of the administered drug is excreted unchanged with the remaining metabolic hydrolytic metabolic products constituting the remainder.

            • Goserelin clearance is reduced in this setting of renal disease and in that case an increase in drug half-life is noted.

              • By contrast, hepatic impairment has relatively minor effects on goserelin pharmacokinetics.

            • Importantly, due to the "white therapeutic window" of goserelin, renal or hepatic insufficiency does not require alteration in patient dosing. ²

      • Mechanism of Action:

        • In 1941 experiments demonstrated that reducing serum testosterone (by castration or estrogen treatment) induced regression of metastatic prostate cancer.⁶  

        • These analogs bind to GnRH receptors (GnRH-R) in the pituitary resulting in an initial increase in Lutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) and testosterone.

        •  LH increases testosterone production by Leydig cells (testicular interstitial cells).

          • FSH increases testicular growth and production of androgen-binding protein by Sertoli cells required for supporting sperm cell maturation.

          • This initial "androgen surge" is associated with the first 3-7 days of treatment.

            • The initial increase (surge) in agonist activity associated with GnRH analog administration may result in a "flare" response due to elevated androgen levels.⁶.

              • This clinical flare may be associated with:

                • Elevated prostate volume

                • Spinal cord compression and

                • Bone pain.

                  • Although no longer common practice, antiandrogen administration has been used to block flare symptoms.

                    • Examples of antiandrogens used for this purpose include flutamide or bicalutamide.^6,3

          • However, the continuous activation of GnRH receptors causes gonatotroph cellular desensitization as well as reduced GnRH-R expression.

            • This response causes a reduction in Leutinizing-Hormone (LH) synthesis, thus halting testicular steroidogenesis.

            • In summary, gonadal androgen synthesis is suppressed due to feedback inhibition of the Hypothalamic-Pituitary-Gonadal axis.⁶

      • Clinical Uses:

        • Goserelin is administered for palliative treatment of advanced prostate cancer (carcinoma of the prostrate) as well as for management of locally confined prostate cancer in combination with other therapeutic approaches.⁵

          • Other labeled indications include palliative treatment of advanced breast cancer, endometrial thinning, and endometriosis.⁵

      • Side-Effects/ Adverse Effects:⁹

        • Numerous side effects associated with goserelin administration have been reported.

          • 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 

    • Leuprolide (Lupron,  Eligard)

      • Overview:

        • GnRH synthetic agonists [goserelin, Zoladex; triptorelin, Trelstar; leuprolide, Lupron], are used in treating prostate cancer.⁶

          • Metastatic prostate cancer may be addressed by androgen deprivation.

            • For example, orchiectomy results in about an 80% response rate in patients.⁷ 

              • Instead of orchiectomy, testicular androgen suppression can be induced by agents such as leuprolide, goserelin (above) and others.

              • Furthermore, principal hormonal management in prostate cancer could typically involve orchiectomy or leuprolide (or related agents), but not both together. 

          • The GnRH synthetic analogs are administered at high-dose as constant release formulation.

            • Depot formulations for luprolide (as well as for the other approved GnRH agonists) allow for durations of action extending from 1 to 6 months.⁶

      • Absorption, Distribution, Biotransformation, Excretion

      • Leuprolide (Lupron) is not active when administered orally and is therefore typically administered subcutaneously or more likely, as a monthly intramuscular depot injection.⁶ 

        • This route of administration allows for a slow, constant release of drug.

        • Using a depot formulation of 3.75 mg, a peak plasma level (4.6-10.2 ng/ml) is obtained in about 4 hours.

        • Plasma concentrations becomes stable after about two days (0.3 ng/ml), maintaining that level for about a month.

          • The steady-state volume of distribution (V_d) is approximately 30 L.

          • This agent exhibits a terminal elimination half-time of about 3 hours.⁶

        • Protein binding is in the range of 45%.¹¹ 

        • Metabolism: The principal metabolite is an inactive pentapeptide (M-1) as well as other smaller inactive peptides.

          •  Leuprolide metabolism does not involve the cytochrome P450 system.¹³

        • Excretion:  About 5% of the intact drug and major metabolite is recoverable in the urine.¹¹  

          • The smaller, inactive peptides of leuprolide are formed as a result of the action of the enzyme peptidase.¹² 

    • Mechanism of Action:

      • In 1941 experiments demonstrated that reducing serum testosterone (by castration or estrogen treatment) induced regression of metastatic prostate cancer.⁶  

      • These analogs bind to GnRH receptors (GnRH-R) in the pituitary resulting in an initial increase in Lutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) and testosterone.

      •  LH increases testosterone production by Leydig cells (testicular interstitial cells).

        • FSH increases testicular growth and production of androgen-binding protein by Sertoli cells required for supporting sperm cell maturation.

        • This initial "androgen surge" is associated with the first 3-7 days of treatment.

          • The initial increase (surge) in agonist activity associated with GnRH analog administration may result in a "flare" response due to elevated androgen levels.⁶.

            • This clinical flare may be associated with:

              • Elevated prostate volume

              • Spinal cord compression and

              • Bone pain.

                • Although no longer common practice, antiandrogen administration has been used to block flare symptoms.

                  • Eamples of antiandrogens used for this purpose include flutamide or bicalutamide.^6,3

        • However, the continuous activation of GnRH receptors causes gonatotroph cellular desensitization as well as reduced GnRH-R expression.

        • This response causes a reduction in Leutinizing-Hormone (LH) synthesis, thus halting testicular steroidogenesis.

          • In summary, gonadal androgen synthesis is suppressed due to feedback inhibition of the Hypothalamic-Pituitary-Gonadal axis.⁶

    • Clinical Uses:

      • Leuprolide is administered for palliative treatment of advanced prostate cancer (carcinoma of the prostrate) as well as for management of locally confined prostate cancer in combination with other therapeutic approaches.⁵

    • Adverse Effects/Toxicities:

      • Numerous side effects associated with leuprolide administration have been reported.

        • 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 

    • Triptorelin (Decapeptyl, Gonapeptyl)¹⁴

      • Overview:

        • Triptorelin is a synthetic GnRH agonist available as either an acetate or a pamolate salt.

        • Triptorelin is an example of a GnRH synthetic agonist [along with goserelin, Zoladex and leuprolide, Lupron], used in treating prostate cancer.⁶

          • Metastatic prostate cancer may be addressed by androgen deprivation. For example, orchiectomy results in about an 80% response rate in patients.⁷ 

            • Instead of orchiectomy, testicular androgen suppression can be induced by agents such as triptorelin (Decapeptyl, Gonapeptyl, Trelstar (pamolate formulation)) and others.

          • Triptorelin pamolate (Trelstar) is a decapeptide, (pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2).¹²

        • Absorption, Distribution, Biotransformation, Excretion:

          • Triptorelin (pamolate) is available for intramuscular depot injection (buttock) at several doses corresponding to differing dosage intervals.⁶

            •  In vitro, triptorelin exhibits more biological activity compared to native GnRH (by about a factor of 100).

              • Triptorelin, when administered as a subcutaneous depot formulation achieves peak serum levels in about 2 hours, a timeframe unaffected by which dosage is chosen (3.75 mg, 11.25 mg or 22.5 mg).

            • The volume of distribution (V_d) for triptorelin is about 30 L.⁶ 

            • Triptorelin is not associated with protein binding.¹⁴ 

          • Metabolic pathways which may be involved in triptorelin degradation remain to be identified but appear unlikely to be cytochrome P450 dependent.⁶,¹⁴

          • Triptorelin is eliminated by both hepatic and renal pathways with about 40% of an administered dose recovered intact in the urine.

            • In patients with hepatic dysfunction, the percentage of intact triptorelin recovered in the urine is increased by about 50%.⁶

         

        • Mechanism of Action:

          • In 1941 experiments demonstrated that reducing serum testosterone (by castration or estrogen treatment) induced regression of metastatic prostate cancer.⁶  

          • These analogs bind to GnRH receptors (GnRH-R) in the pituitary resulting in an initial increase in Lutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) and testosterone.

          •  LH increases testosterone production by Leydig cells (testicular interstitial cells).

            • FSH increases testicular growth and production of androgen-binding protein by Sertoli cells required for supporting sperm cell maturation.

            • This initial "androgen surge" is associated with the first 3-7 days of treatment.

              • The initial increase (surge) in agonist activity associated with GnRH analog administration may result in a "flare" response due to elevated androgen levels.⁶.

                • This clinical flare may be associated with:

                  • Elevated prostate volume

                  • Spinal cord compression and

                  • Bone pain.

                    • Although no longer common practice, antiandrogen administration has been used to block flare symptoms.

                      • Eamples of antiandrogens used for this purpose include flutamide or bicalutamide.^6,3

            • However, the continuous activation of GnRH receptors causes gonatotroph cellular desensitization as well as reduced GnRH-R expression.

            • This response causes a reduction in Leutinizing-Hormone (LH) synthesis, thus halting testicular steroidogenesis.

              • In summary, gonadal androgen synthesis is suppressed due to feedback inhibition of the Hypothalamic-Pituitary-Gonadal axis.⁶

          • Clinical Uses:

            • Triptorelin  is administered for palliative treatment of advanced prostate cancer (carcinoma of the prostrate) as well as for management of locally confined prostate cancer in combination with other therapeutic approaches.⁵

          • Adverse Effects/Toxicities:

            • Numerous side effects associated with triptorelin administration have been reported.

              • 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