IC9: Pharmacology of selected drugs for endocrine cancers

Question 1

What is Tamoxifen indicated for?

Answer 1

Breast cancer

Question 2

What is the MOA of Tamoxifen?

Answer 2

• Selective estrogen receptor modulator (SERM)
• It competitively blocks endogenous estrogen binding to the ER in the target tissue. The tamoxifen-ER complex alters estrogen-responsive gene expression, thus preventing cell activation and proliferation
• Has anti-estrogenic and estrogenic effects
• Has tissue-specific effects

Question 3

Why does Tamoxifen have both estrogenic and anti-estrogenic effects?

Answer 3

Tamoxifen exists in cis- and trans- stereoisomers. The cis-isomer has estrogenic activity while the trans-isomer has anti-estrogenic activity

Question 4

What is the metabolism pathway of Tamoxifen?

Answer 4

• Phase 1: Hydroxylation, N-oxidation, dealkylation
• Phase 2: glucuronidation, sulfation
• Major pathway of metabolism: N-demethylation (catalysed by CYP3A4)
• One of the major metabolites: N-desmethyltamoxifen
• Has active metabolites by CYP2D6: 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are minor metabolites that exhibit affinity for the estrogen receptor that is greater than that of tamoxifen

Question 5

Are there any drug or food interactions with Tamoxifen?

Answer 5

• Grape fruit (juice) inhibits CYP3A4
• Diphenhydramine can inhibit CYP2D6

Question 6

6

What are the side effects of Tamoxifen?

Answer 6

• Hot flashes
• Increased risk of endometrial cancer
• Venous thromboembolic events (DVT)
• Menstrual irregularities
• Vaginal bleeding and discharge
• Nausea, vomiting

Question 7

Toxicity of Tamoxifen

Answer 7

High doses could lead to acute neurotoxicity (tremor, hyperflexia, unsteady gait, dizziness)

Question 8

What is Pembrolizumab indicated for?

Answer 8

Cervical cancer

Question 9

MOA of Pembrolizumab

Answer 9

• Cancer cells produce a particular protein called PD-L1 that interacts with PD-1, which is important for immune cells to recognise cancer cells. The cancer cell creates ligand interaction to fool the immune cell, preventing it from triggering its immune response
• Pembrolizumab is a PD-1 blocker, which binds to PD-1, releasing PD-1 pathway-mediated inhibition of T-cell activities

Question 10

6

Side effects of Pembrolizumab

Answer 10

• Infusion-related side effects like rash and itchiness
• Nausea
• Diarrhoea
• Fatigue
• Joint pain
• (Life-threatening) immune-related inflammation on lung, endocrine organs, kidney, liver, sepsis

Question 11

Contraindications of Pembrolizumab

Answer 11

• Patient taking corticosteroids or immunosuppressants (stop before starting Pembrolizumab)
• Pregnant women (increases risk of miscarriage)
• Patients who have a history of severe reaction to another antibody therapy, other illnesses (consult doctor)

Question 12

What is Leuprorelin indicated for?

Answer 12

Prostate cancer

Question 13

MOA of Leuprorelin

Answer 13

• Synthetic GnRH analogue acting as an agonist at pituitary GnRH receptors
• Decreased androgen (testosterone) production in testes, minimising the stimulatory effect on androgen-sensitive cancer cell, causing cancer cell to undergo apoptosis
• Continuous administration inhibits FSH and LH release, suppressing androgen synthesis

Question 14

Side effects of Leuprorelin

Answer 14

• Local pain at injection site
• Hyperglycemia
• Hyperlipidemia
• GI disturbances
• Altered mood
• Headaches/migraines
• Flushes
• Loss of libido, impotence

Question 15

Contraindications of Leuprorelin

Answer 15

• Hypersensitivities to Leuprorelin or other GnRH agonists
• Pre-existing heart disease
• Patients at risk of osteoporosis e.g. elderly

Question 16

What is the indication of Bicalutamide?

Answer 16

Prostate cancer

Question 17

Can Bicalutamide be used as monotherapy?

Answer 17

No, it should be prescribed together with Leuprorelin for prostate cancer. This is because it blocks AR, causing increased LH secretion and thus higher serum testosterone levels

Question 18

MOA of Bicalutamide

Answer 18

• Anti-androgen
• Acts competitively to antagonise androgen receptor
• Inhibits nuclear translocation of the AR and interaction of the AR with the promoter at the AR response element. The inhibition of AR-dependent transcription impairs cell proliferation and triggers apoptosis in cancer cells
• Prostate growth depends on androgens, so androgen deprivation decreases progression of prostate cancer

Question 19

Metabolism of Bicalutamide

Answer 19

• Stereoselective
• S-bicalutamide [inactive]: glucuronidation
• R-bicalutamide [active]: hydroxylation (CYP3A4), followed by glucuronidation

Question 20

5

Side effects of Bicalutamide

Answer 20

• Gynecomastia
• Sexual dysfunction
• Fatigue
• GI disturbance
• Seizure (rare)