pharmacology of drugs for endocrine cancers and disorders

Question 1

Name the drug used to treat breast cancer?

Answer 1

Tamoxifen (selective estrogen receptor modulator)

Question 2

Name the drug used to treat cervical cancer?

Answer 2

Pembrolizumab (biologic)

Question 3

Name the drug(s) used to treat prostate cancer?

Answer 3

Leuprorelin (GnRH analogue) + bicalutamide (AR antagonist)

Question 4

What are the properties of tamoxifen? including the indication, MOA, dosing, PK/PD, DDI, S/E, and monitoring

Answer 4

indication: breast cancer, chemoprophylaxis of breast cancer in women at high risk

route: PO (good oral bioavailability)

MOA: competitively inhibits endogenous estrogen from binding to the estrogen receptor in the breast, thus altering estrogen-responsive gene expression, hence preventing cell activation and proliferation

PK/PD: hepatic metabolism, metabolised by CYP3A4 and CYP2D6; CYP2D6 produces active metabolites that exhibit greater affinity to the estrogen receptor than tamoxifen

DDI: inhibitors/inducers of CYP3A4 and CYP2D6

S/E: hot flushes, increased risk of endometrial cancer, increased risk of venous thromboembolic events (e.g. DVT), menstrual irregularities, vaginal bleeding and discharge, N/V, neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness) at high doses

Question 5

What are the properties of pembrolizumab? including the indication, MOA, dosing, PK/PD, DDI, S/E and monitoring

Answer 5

indication: cervical cancer

route: IV (infusion over 30 mins)

dose: IV 200mg every 3 weeks (may last longer than 8 months)

MOA: binds to and blocks PD-1 receptor expressed on T cell, thus inhibiting the binding of PD-L1 expressed on cancer cells to the PD-1 receptor expressed on T cells, enabling the activation of T cell activity against cancer cell

PK/PD: non-specific protein catabolism; no metabolic DDIs expected

S/E: infusion site reactions, e.g. rash/pruritis, fatigue, diarrhoea, nausea, joint pain, immune-related inflammation on lungs, endocrine glands, liver, kidney and sepsis (life threatening)

Question 6

Name the contraindications for pembrolizumab

Answer 6

Patient taking corticosteroids or immunosuppressants (may reduce the efficacy of pembrolizumab), pregnant women (increases risk of miscarriage), history of severe hypersensitivity to other biologics

Question 7

What are the signs and symptoms of prostate cancer?

Answer 7

LUTS (dysuria, increased urinary frequency, feeling of incomplete urination, weak urinary flow), dark reddish urine, back pain, weak or swollen limbs

Question 8

What are the properties of leuprorelin (also known as leuprolide) ? including indication, MOA, route, dosing, PK/PD, DDI, S/E and monitoring

Answer 8

indication: prostate cancer

MOA: GnRH (gonadotropin releasing hormone) analogue, hence acting as an agonist at the anterior pituitary GnRH receptors. When given continuously (NOT intermittently), suppresses the secretion of LH and FSH from the anterior pituitary, hence decreasing the stimulation of testicles to produce androgens (testosterone)

route: SC/IM given as a single dose long-depot, at 1, 3 or 4 months intervals

PK/PD: non-specific peptide catabolism; no metabolic DDIs expected

S/E: injection site reaction, e.g. local pain and redness, hot flushes during first few weeks of therapy, headache/dizziness, GI disturbances, altered mood, decreased libido, hyperglycemia

Monitoring: assess for PSA (prostate-specific antigen) count in the first few weeks of therapy (should decrease significantly, target is <1), to measure LSH, FSH and testosterone levels after 4 weeks of therapy

Question 9

Name the contraindications for leuprorelin

Answer 9

hypersensitivty to leuprorelin or other GnRH agonists, pre-existing heart disease, risks for osteoporosis

Question 10

What are the properties of bicalutamide? including indication, route, dosing, MOA, PK/PD, DDI, S/E and monitoring

Answer 10

indication: used in combination with GnRH analogue (e.g. leuprorelin), in order to mitigate the effects of the initial testosterone surge (tumour flare), in treatment of metastatic prostate cancer, and in combination with surgery/radiation therapy for locally advanced disease *

*do NOT use bicalutamide as monotherapy for prostate cancer

route: PO (good oral bioavailability)

MOA: competitive androgen receptor antagonist; inhibits nuclear translocation of androgen receptor and the interaction of the androgen receptor with the androgen-response element within the promoter. This inhibits androgen dependent transcription, resulting in impaired cell proliferation and triggering apoptosis in cancer cells (prostate growth depends on androgens, so androgen deprivation decreases the progression of prostate cancer)

PK/PD: metabolised by the liver

S/E: hot flushes, N/V/ decreased libido / ability to have sex, constipation / diarrhoea, mild swelling of ankles/legs/foot

Question 11

Why should bicalutamide NOT be used as monotherapy in prostate cancer?

Answer 11

Bicalutamide is an androgen receptor antagonist, hence preventing the activation of prostate cancer cells. However, the initial negative feedback will cause an increase in LH secretion and increase in serum testosterone levels

Question 12

Name the contraindications of bicalutamide?

Answer 12

Women, children, hypersensitivity to bicalutamide