IC9 Pharmacology of Endocrine Cancer Drugs

Question 1

What medications (with drug class) are indicated for breast cancer & its chemoprevention, cervical cancer and prostate cancer?

Answer 1

Breast - Tamoxifen (Selective estrogen receptor modulator)

Cervical - Pembrolizumab (Death Receptor-1 Blocker)

Prostate - Leuprorelin (Synthetic GnRH analog) + Bicalutamide

Question 2

Which isomer has estrogenic activity for tamoxifen?

Answer 2

Cis isomer has estrogenic activity
Trans isomer has anti-estrogenic activity

Question 3

What types of antibody can pembrolizumab be?

Answer 3

Humanized Ab (Mouse)
Recombinant – From CHO cells

Question 4

What is the MOA of tamoxifen?

Answer 4

Competitive inhibition of ER with endogenous estrogen in target tissue (breasts) ⇒ Tamoxifen-ER complex alters estrogen-responsive gene ⇒ Reduced activation/proliferation

Steps:
1) Binds to ER in the receptor bound form or in the cytoplasm
2) Competes with estrogen for the ER
3) Once bound, the HSP90 dissociates and thus allows dimerisation of the ER
4) Deactivation of only one of the 2 transcription sites on the ER (the AF2, leaving the AF1 site available)
5) The complex translocates into the nucleus and binds to the Estrogen responsive element (ERE). The activated AF1 site on the ER recruits CoA and mediates RNA polymerase transcription.
6) Since partial inactivation, there is a reduction in cancer cell division

Question 5

What is the MOA of Pembrolizumab?

Answer 5

PD-1 pathway-mediated inhibition of T cell activities (Immunomodulatory effect)
⇒ Inhibits cancer metastasis

Question 6

What is the MOA of leuprorelin and bicalutamide?

Answer 6

Leuprorelin: Agonist at pituitary GnRH receptor ⇒ testosterone production, the positive effect on androgen-sensitive prostate cancer cells; Continuous administration FSH & LH release

Bicalutamide: Androgen receptor antagonist (Not monotherapy) – Inhibits nuclear translocation of AR & interaction with promoter / response element

Question 7

What are the routes of administration for the endocrine cancer drugs?

Answer 7

Tamoxifen - Oral
Pembrolizumab - IV (q3wk for > 8 months)
Leuprorelin - SC/IM (At 1, 3, 4 month interval)
Bicalutamide - Oral

Question 8

Which endocrine cancer drugs are plasma protein bound and what’s the volume of distribution / sites with higher concentrations?

Answer 8

Tamoxifen - Bound, High Vd in breast, uterus, liver, lung, kidney, pancreas, ovary than in circulation

Pembrolizumab - Not bound, Small Vd with limited extravascular distribution

Leuprorelin - No data

Bicalutamide - Bound to albumin (High)

Question 9

How are the endocrine drugs eliminated from the body?

Answer 9

Tamoxifen
- Metabolism (Hepatic)
1) Major metabolite: N-desmethyl tamoxifen (CYP3A4)
2) Other active metabolite: 4-OH tamoxifen (CYP2D6)
3) Ultimately, both can be converted to endoxifen (Most active metabolite)
- Excretion: Feces

Pembrolizumab = Metabolism
- Non-specific catabolism (General protein degradation routes)
- Factors influence clearance: Albumin and bilirubin levels, types of cancer, gender (lower CL in females)

Leuprorelin
- Proteolytic degradation, not hepatic
- Low urine excretion

Bicalutamide
- Liver Metabolism – Stereoselective (Chiral)
(S)-Bicalutamide [inactive] – glucuronidation
(R)-Bicalutamide [active] – hydroxylation (CYP 3A4) glucuronidation
- Excretion: Bile, urine

Question 10

What are the 6 ADRs of tamoxifen?

Answer 10

1. Hot flashes
2. ↑ risk of endometrial cancer
3. Venous thromboembolic events (DVT)
4. Menstrual irregularities
5. Vaginal bleeding/discharge
6. Nausea, vomiting

Question 11

What are the ADRs of Pembrolizumab?

Answer 11

Infusion-relation S/Es such as Rash, itchiness

Fatigue, Diarrhea, Nausea, Joint pain, (Life threatening) Immune- related inflammation on lung, endocrine organs, liver, kidney, sepsis.

Question 12

What are the ADRs of Leuprorelin Bicalutamide?

Answer 12

Leuprorelin
Local pain @ injection site, Flushes, Headaches/migraine, GI, Altered mood, Hyperglycemia, Hyperlipidemia, Libido loss, impotence

Bicalutamide:
Gynecomastia, Sexual dysfunction, Fatigue, GI, Seizure (rare)

Question 13

What are the DDIs or CI of the endocrine cancer drugs?

Answer 13

Tamoxifen
CYP3A4 inhibitors: Grapefruit
CYP2D6 inhibitors: Diphenhydramine

Pembrolizumab
CI: Corticosteroids / Immunosuppressants; Pregnancy; History of severe reaction to Ab therapy

Leuprorelin
CI: Hypersensitivity, pre-existing heart disease, osteoporosis risk

Question 14

What are some special considerations for the endocrine cancer drugs?

Answer 14

Tamoxifen:
High doses ⇒ Acute neurotoxicity (tremor, dizzy, hyperreflexia, unsteady gait)

Leuprorelin
Monitor PSA in 1st few weeks, LH, FSH, testosterones after 4wks