Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Hormonal Anticancer Drugs: 

  • Antiandrogen Drugs ⁵

    • Overview:

      • These agents, the nonsteroidal first-generation antiandrogen drugs, were initially employed to inhibit androgen receptor binding.¹¹

        • These drugs were approved to limit flare associated with the initial serum testosterone increase due to GnRH agonists/antagonist treatment.

        • Given alone, antiandrogens increased testosterone levels but compared to testosterone-lowering drugs, administration resulted in:

          • Less hot flushes

          • Reduced libido effects

          • Reduced muscle wasting

          • Reduced bone loss

          • More limited personality changes.

        • A clinical problem, gynecomastia, may be mitigated through administration of tamoxifen or by "prophylactic breast irradiation."¹¹ 

        • Androgen receptor antagonists (flutamide, bicalutamide, nilutamide and enzalutamide) are considered of limited effectiveness when used as monotherapy, as result of induced higher serum testosterone levels secondary to increased Leutinizing-Hormone (LH) secretion.

          • Accordingly, flutamide and related agents are used in combination with the GnRH analog for metastatic prostate cancer therapy.¹³ 

          • Antiandrogen drugs used alone result in suboptimal cancer-specific outcomes.

            • For example, bicalutamide, even at relatively higher doses, reduced time to cancer progression and conferred inferior survival when compared to surgical castration in patients with documented metastatic disease.¹¹

        • Even when combined with GnRH analogs are surgical orchiectomy procedures, use of first-generation antiandrogen agents (flutamide et al.) did not result in improvement in treating cancer patients compared to androgen deprivation therapy (ADT) alone.¹¹ 

          • Due to this finding, first-generation antiandrogen drugs have a limited use, protection against flare during the first 2-4 weeks of treatment.

          • However, important enhancement using time to progression and overall survival endpoints, documented in large-scale clinical trials have been noted when androgen deprivation therapy (ADT) is administered in combination with docetaxel or with abiraterone + prednisone.

          • This combination was compared to ADT administration alone. Docetaxel was the initial systemic treatment found to prolong life in patients with metastatic castration-resistant prostate cancer.¹¹

           

      • Flutamide (Eulexim and others)

        • Overview:

          • Flutamide acts by inhibiting androgen uptake or androgen binding at target sites.

          • This drug is classified as a nonsteroidal antiandrogen agent.

           

        • Flutamide (Eulexim)

        • Absorption, Distribution, Biotransformation, Excretion:

          • Flutamide (Eulexin) oral administration results in virtually complete absorption from the G.I. tract.¹²

          • Following absorption, flutamide undergoes substantial first-pass metabolism (metabolism occuring prior to the parent compound reaching the systemic circulation).

            • Flutamide is metabolized by the hepatic cytochrome P450 drug metabolizing system, primarily by the CYP1A2 enzyme isoform.¹² 

              • The major metabolite is a hydroxylated derivative, 2-hydroxyflutamide, the active form of the drug.

              • Another important metabolite is formed by hydrolysis of 2-hydroxyflutamide, 3-trifluoromethyl-4-nitroanaline.

            • The major metabolite, 2-hydroxyflutamide exhibits higher affinity interaction with the androgen receptor compared to flutamide and has been described as the more powerful antiandrogen.¹²  

              • With respect to elimination pharmacokinetics 2-hydroxyflutamide shows and elimination half-life between about 6-10 hours.^5,12

          • Excretion of flutamide and metabolites is mainly in the urine (feces, 4%).⁵

        • Mechanism of Action: 

          • Flutamide, which may be administered as part of a regimen useful in managing prostatic cancer, acts as a competitive androgen receptor antagonist.¹⁴ 

            • Flutamide is classified as a "potent antiandrogen."

        • Clinical Uses:

          • Flutamide is considered one of the older antiandrogen agents, however, and may be less effective relative to current antiandrogen drugs.

            • Possibly, older antiandrogen drugs might be appropriate in a more limited setting, for example in patients with "low prostate cancer disease burden" or "limited therapy options."⁵

            • Flutamide administration may result in some improvement in prostate cancer patients not having received previous endocrine treatment.¹⁴

        • Adverse Effects/Toxicities:

          • Adverse reactions include those categorizesd as endocrine and metabolic.⁵ 

          • Common side effects associated with flutamide administration involve:¹⁵

            • Diarrhea

            • Nipple tenderness

            • Breast tenderness.

          • Side effects lasts frequently noted include:

            • Nausea

            • Vomiting

            • Liver toxicity.

              • However, liver toxicity (hepatotoxicity), although uncommon (3/10,000 patients) may be fatal, thus requiring careful monitoring of serum aminotransferases during flutamide administration.¹⁵

      • Bicalutamide (bye ka LOO ta mide, Casodex)⁸

        • Overview

          • Bicalutamide is a competitive inhibitor, inhibiting the binding of both testosterone and dihydrotestosterone at the androgen receptor.

            • This agent is classified as a pure, nonsteroidal androgen receptor antagonist.

            • Such antagonism prevents testosterone stimulation of prostate cancer cell proliferation.⁸

          • For management of advanced prostate cancer (USA):

            • Bicalutamide (Casodex) is usually administered once-a-day in combination with a GnRH analog or following surgical castration.¹⁵

          • Bicalutamide  is provided as a racemic mixture.

            • The antiandrogenic property is associated with the (R)-enantiomer which exhibits substantially more affinity for prostatic androgen receptors than noted with hydroxyflutamide.¹⁵ 

            •  

              Bicalutamide (Casodex)

        • Absorption, Distribution, Biotransformation, Excretion:

          • Bicalutamide (Casodex) may be administered once-a-day typically along with a GnRH agonist.¹ 

          • The bicalutamide formulation is that of a racemic mixture.¹²

            • The (S)-enantiomer is devoid of antiandrogenic properties.

          • Antiandrogenic effects are mediated by the (R)-enantiomer which exhibits low absorption, not influenced by food.

            • The half-life (terminal) of elimination is about 5-6 days.

          • The active enantiomer, (R)-bicalutamide, is usually present at substantially higher plasma levels given that the (S), the inactive form, is cleared from the plasma rapidly, following rapid absorption.

          • Bicalutamide binds extensively to plasma proteins, especially albumin.

            • Bicalutamide is metabolized both by glucuronidation (phase II) and by hydroxylation (Phase I), using the liver microsomal cytochrome P450 drug metabolizing system.

              • The (S)-form is metabolized by glucuronidation; whereas, the (R)-form is metabolized by the cytochrome P450 system (hydroxylation, using the CYP3A4 cytochrome P450 isoform) probably followed by glucuronidation.^12,15

          • Bicalutamide metabolites are found, in almost equal proportion, in feces and urine.¹²

        • Mechanism of Action:

          • Bicalutamide, which may be administered as part of a regimen useful in managing prostatic cancer, acts as a competitive androgen receptor antagonist.¹⁴ 

            • Bicalutamide is classified as a "potent antiandrogen."

        • Clinical Uses:

          • Bicalutamide is used in prostate cancer therapy.

            • However, bicalutamide as well as flutamide are not approved as monotherapy.

            • Accordingly, bicalutamide would be most commonly administered along with GnRH agonists in the setting of prostate cancer management.

            • Bicalutamide administration as a single drug is associated with inferior survival profiles; for example, given alone, bicalutamide clinical results are notably worse compared with surgical or medical castration.¹⁵

        • Adverse Effects/Toxicities:

          • Numerous adverse reactions occur as result of bicalutamide administration.

            • These adverse effects are associated with almost all major organ systems e.g. cardiovascular, central nervous system, gastrointestinal and so forth.⁸

            • Prominent toxicities include:

              • Vasomotor instability

              • Gynecomastia

              • Mastodynia (breast pain)¹⁵

    • Nilutamide (ni LOO ta mide, Nilandron, Anadron)⁹

      • Nilutamide is an androgen receptor antagonist, blocking testosterone action.

        • As a result, nilutamide prevents or limits androgen responses.

        • Nilutamide is classified as a nonsteroidal antiandrogen drug.

        •  

          Nilutamide (Nilandron, Anadron)

           

      • Nilutamide (Nilandron, Anadron) is another antiandrogen which may be used in prostate cancer patients.

        • Absorption: nilutamide is given once daily by oral administration.¹

        • Biotransformation: the elimination half-time (t_1/2) of nilutamide is about two days.

          • Five metabolic products of nilutamide have been identified.

        • Excretion: Nilutamide metabolites are excreted in the urine.

        • Side-effect/toxicities: This agent may induce night blindness (frequency of occurrence: 25%-40%) and is associated with pulmonary toxicity.

          • In addition to night blindness and pulmonary toxicity (interstitial pneumonitis occurs rarely)

          • Other side effects are mild nausea and reduced alcohol tolerance noted in about 5%-20% of patients taking nilutamide.¹

          • As a result, the drug has seen limited use.^{1, 3}