Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Hormonal Anticancer Drugs: 

  • Overview:  Cytochrome P450 enzyme, CYP17 inhibitor⁵

    • Abiraterone acteate⁵   (Zytiga: abiraterone acetate + prednisone; Yonsa:  abiraterone acetate + methylprednisolone)

  • Abiraterone acetate is classified as an anti-androgen agent given that it prevents or limits formation of testosterone precursors: dehydroepiandrosterone (DHEA) and anthracenedione.

    • The mechanism of action involves a selective and a reversible inhibition of a cytochrome P450 enzyme, CYP17 (17 α-hydrolase/C17,20-lyase).

    • CYP17 is an enzyme essential for catalysis of androgen biosynthesis.

      • The enzyme is found in testicular, adrenal and prostate cancer cells. abiraterone acetate is typically combined with prednisone or methylprednisolone.

  • Abiraterone acetate is a steroidal prodrug which is converted into an active 3β-hydroxy metabolite in esterase-catalyzed reactions¹ .

    • Abiraterone is typically combined with prednisone in treating castration-resistant prostate cancer (CRPC) patients who have not previously received chemotherapy or who have received previous docetaxel¹ .

  • Following castration, androgen receptor signaling even though steroid levels are low continues to promote prostate cancer cell proliferation.

    • Androgen receptor activation may result from binding of androgens produced from nongonadal sources or as a result of androgen receptor (AR) genetic mutations or amplifications.

    • Examples of nongonadal androgen sources include adrenal glands and prostate cancer cells.

      • For instance, anthracenedione synthesized in adrenal glands is transformed to testosterone in tumors and peripheral tissues.¹ 

  • The rationale of using androgen synthesis inhibitors is their ability to counteract androgen receptor activation in the castrate state.¹ 

    • Abiraterone acetate (FDA approval, 2011) administered for treatment of metastatic castration resistant prostate cancer (mCRPC) following docetaxel treatment extended survival by about four months.⁶

    •  

      Abiraterone for metastatic, hormone sensitive, prostate cancer

      Attribution: Petrylak DP Abiraterone for metastatic, hormone sensitive, prostate cancer https://www.youtube.com/watch?v=pHa9fYhncjg (7/2017) ecancer Youtube Channel:  https://www.youtube.com/channel/UCGb_Xmf5mzvyXC7NOjsonkg

   

  • Abiraterone acteate

     

  • Absorption, Distribution, Biotransformation, Excretion

    • Absorption:

      • Abiraterone is administered orally, typically in combination with prednisone in order to limited adrenal suppression.

      • This agent should be preferably taken on an empty stomach.¹

        • Maximal plasma concentration of the active agent abiraterone, following oral administration of abiraterone acetate, occurs in about two hours following administration.¹⁰

        • Given the poor drug solubility, the presence of food significantly and inconsistently alters drug absorption.

          • For example, consumption of low-fat food increases absorption by about 6 times.¹⁰ 

            • By contrast, consumption of a high-fat meal may increase absorption up to 17 times.

        • Accordingly, food should not be consumed within one hour before or 2 hours after abiraterone administration.¹⁰

      • Bioavailability appears to be increased by food resulting in higher systemic drug levels.¹⁰

    • Distribution:

      • Abiraterone is substantially bound (greater than 99% to plasma proteins, albumin as well as α-1 acidic glycoprotein.¹²  

      • The steady-state volume of distribution (apparent) is about 19,000 +/- 13,000 L (mean +/- s.d.)¹² 

        • This large volume of distribution (Vd) is indicative of very poor solubility.¹⁰

    • Biotransformation:¹⁰

      • Following activation from the prodrug precurser abiraterone acetate, abiraterone is subject to metabolism.

        • The major circulating abiraterone metabolites are sulfate derivatives: abiraterone sulfate and N-oxide abiraterone sulfate.

        • Abiraterone sulfate formation is catalyzed by sulfotransferase family 2A Member 1 (SULT2A1); whereas, the N-oxide abiraterone sulfate is formed in a reaction catalyzed by the cytochrome P450 isoform CYP3A4.¹⁰

      •  

        Abiraterone Acetate Metabolism¹³

        Attribution:  Eboers S Stapaerts J Mols R Snoeys J Tack J Annaert Augustinjs P  The Effect of Food on the Intraluminal Behavior of Abiraterone Acetate in Man.  Journal of Pharmaceutical Sciences 105:  2974-2981, 2016 Figure 1 (slightly modified)  https://www.jpharmsci.org/article/S0022-3549(16)00436-6/pdf

    • Excretion:¹⁰

      • Elimination half-life is about 15 hours typically. However, in patients with some hepatic impairment extended half-life of elimination is noted (18-19 hours).¹⁰
        Following oral dosing (in a population of castration resistant prostate cancer patients), most of the administered agent is recovered in the feces as unchanged abiraterone acetate (55%) and abiraterone (22%).^10,14 

      • An additional 5% is found in the urine.¹⁴

    • Mechanism of Action

      • Abiraterone reversibly inhibits both 17α-hydroxylase and C-17,20-lyase (CYP17A1) enzymatic activity in:

        • Testicular

        • Adrenal, and

        • Prostate cancer tissue.

      • CYP17A1 inhibition:

        • Decreases pregnenelone and progesterone conversion to their corresponding 17 α-hydroxy derivatives and

        • Decreases DHEA (dehydroepiandrosterone) synthesis and

        • Decreases androstenedione synthesis.

    • Sites of Enzyme Inhibtion by Abiraterone Acetate¹⁵

      Attribution:  Thakur A Roy A Ghosh A Chhabra M Banerjee S  Abirateone acetate in the treatment of prostate cancer. Biomedicine & Pharmacotherapy 201:  211-218, May 2018. https://pubmed.ncbi.nlm.nih.gov/29494958/ Figure 2 (slightly modified)

       

    • Clinical Uses:¹¹

      • Initially, abiraterone was FDA approved for use in management of metastatic castration-resistant prostate cancer, as secondary hormonal treatment.

        • A clinical study, "Cougar-301" compared clinical results in patients previously having received chemotherapy with docetaxel to treatment with abiraterone acetate with prednisone or placebo.

          • The result indicated that abiraterone compared to placebo conferred an improved overall survival (14.8 months versus 10.9 months).

          • Abiraterone was also shown to be associated with overall improved survival when comparing patients, not having received prior docetaxel chemotherapy, but receiving either placebo or abiraterone acetate with prednisone.

        • In 2017 clinical trial results indicated a role for abiraterone acetate in management of metastatic castration-sensitive prostate cancer. In these studies ("LATITUDE") patients began androgen deprivation therapy and after three months either androgen deprivation therapy (ADT) was continued as sole therapy or abiraterone acetate with prednisone was added.

          • Addition of abiraterone improved overall survival.

      • Accordingly, in many men with metastatic castration-sensitive prostate cancer, newly diagnosed, standard of care involves combination of androgen deprivation therapy with abiraterone acetate or docetaxel.¹¹

      • Toxicities/Adverse Effects:¹ 

        • Hepatotoxicity	Joint Swelling	Low Potassium	Diarrhea	Cough
          Vasomotor symptons	Urinary Frequency	Dyspepsia	Upper Respiratory Tract Infection	Arrhythmia

          • Many of the above side effects are related to the principal abiraterone acetate toxicity, mineralocorticoid excess.

            • These toxicities include:

              • Hypertension

              • Fluid excess, and

              • Hypokalemia.

            • Blockade of the cytochrome P450 isoform CYP17A1 results in increased adrenocorticotropic hormone (ACTH).

              • This increase in ACTH increases level of corticosterone and deoxycorticosterone.

              • Coadministration of steroids may mitigate adverse effects.