Pharmacology - Endocrine Cancers Flashcards
What is tamoxifen indicated for?
- Early and metastatic breast cancer, in both pre and post-menopausal women
- May be useful in chemoprevention of breast cancer in women at high risk
- Reduces severity of osteoporosis but is not specifically used for osteoporosis due to availability of agents with superior side effect profiles
What is the mechanism of action of tamoxifen?
- Competitively blocks endogenous estrogen binding to the estrogen receptor in the target
- Tamoxifen then deactivates the AF2 transcription site (AF1 site is still active), which then serves as a partial blocker to alter estrogen-responsive gene expression → ↓ cancer cell activation & proliferation
- Exhibits estrogenic (cis-isomer) and anti-estrogenic (trans-isomer) effects
- Exhibits tissue-specific effects
What is the bioavailability of tamoxifen?
~100%
How is tamoxifen absorbed?
Rapidly and extensively absorbed in intestine
Does tamoxifen bind to plasma proteins?
Yes, >98%
What is the Vd of tamoxifen?
50-60L/kg
How does tamoxifen distribute in the body?
Concentrates well in the breast, uterus, liver, kidney, lung, pancreas, ovaries (uterus cons are 2-3x of circulatory conc, breast conc is 10x)
What is the elimination half-life of tamoxifen?
5-7 days
How is tamoxifen metabolised?
CYP3A4 -N-desmethyl-tamoxifen
CYP2D6 - 4-OH-tamoxifen
both get metabolised by the other CYP enzyme to endoxifen
Phase 1: Hydroxylation, N-oxidation, dealkylation
Phase 2: Glucuronidation, sulphation
What are the adverse effects of tamoxifen?
- Hot flashes (non-dose related)
- Increases risk of endometrial cancer
- Venous thromboembolic events (DVT)
- Menstrual irregularities
- Vaginal bleeding and discharge
- Nausea, vomiting
What are the effects of tamoxifen toxicity?
Acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness)
What is the MOA of pembrolizumab?
Binds to PD-1 on T cells to block PD-L1 on cancer cells from binding to PD-1 – PD-L1 binding to PD-1 inhibits T cell activation so that cancer cells can evade immune response (inhibited by Pembrolizumab)
How is pembrolizumab administered?
IV
What is the Vd of pembrolizumab?
~7L - small because it is a protein molecule
What is the half-life of pembrolizumab?
~27 days
How long does it approximately take for pembrolizumab to reach Css?
19 weeks
How is pembrolizumab cleared?
Cleared from circulation through non-specific catabolism (because it is a protein)
What are the adverse effects of pembrolizumab?
- Infusion related SEs – rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, fever
- Fatigue
- Diarrhoea
- Nausea
- Joint pain
- (Life-threatening) Immune related inflammation on lung, endocrine organs, liver, kidney
- (Life-threatening) Sepsis
What are the contraindications for pembrolizumab?
- Taking corticosteroids or immunosuppressants – stop before starting pembrolizumab (starting afterwards is fine)
- Pregnancy – may inc miscarriage risk
- Hx of severe reaction to another antibody therapy eg hypersensitivity
- Hx of other illnesses – infection, liver/kidney diseases etc (consult dr – risk of opportunistic infection)
What is leuprorelin indicated for?
Prostate cancer
What is the MOA of leuprorelin?
- A synthetic GnRH analogue – acts as agonist at pituitary GnRH receptors
- Decreases androgen (testosterone) production in testes to minimise stimulation of androgen-sensitive prostate cancer cells so that the cancer cells undergo apoptosis
- Continuous administration decreases FSH and LH release to suppress androgen synthesis (as compared to intermittent GnRH which increases FSH and LH instead)
How is leuprorelin administered?
SC or IM as a single-dose long-acting depot (interval can vary – 1, 3 or 4/12)
How long does it take for leuprorelin to reach Cmax?
1-3h
How long does it take for leuprorelin to reach Css?
4 weeks
What is the Vd of leuprorelin?
Vd ~27L after IV
Does leuprorelin bind to plasma proteins?
In-vitro displayed ~45% plasma protein binding
How is leuprorelin metabolised?
Degraded proteolytically (potentially by peptidases) into inactive peptides
What is the half-life of leuprorelin?
~3h
How is leuprorelin excreted?
<5% by urine
What are the adverse effects of leuprorelin?
- Local pain and redness at injection site (~10% of cases)
- Hot flushes during first few weeks of Tx
- Headaches/dizziness
- GI disturbances
- Altered mood
- Hyperglycemia
- Decreased libido (may need to take not depending on whether patient is still sexually active)
What are the contraindications for leuprorelin?
- Hypersensitivity to Leuprorelin or other GnRH agonists
- Pre-existing heart disease
- Patients with risk for osteoporosis
What are the indications for bicalutamide?
- Prostate cancer
- Androgen deprivation therapy – used during initiation of androgen deprivation therapy w an LHRH agonist to reduce the symptoms of tumor flare in metastatic prostate cancer patients
- For locally advanced disease – in conjunction w radiation tx or surgery (start bicalutamide first, then see if response is enough to not need further radiation or surgery)
What is the MOA of bicalutamide?
- Competitively antagonises androgen receptor
- Inhibits nuclear translocation of the androgen receptor and interaction of the androgen receptor response element – impairs cell proliferation and triggers apoptosis in cancer cells
- Androgen deprivation decreases prostate growth rate, thus slowing down progression of prostate CA
How is bicalutamide absorbed?
Well absorbed orally, food does not affect F
Does bicalutamide bind to plasma proteins?
Yes, highly plasma protein bound
(racemic mixture 96%, R-bicalutamide >99%)
How is bicalutamide metabolised?
Extensively metabolised in the liver, T1/2 ~6 days (R-isomer)
- S-isomer (inactive) rapidly cleared by glucuronidation
- R-isomer (active) slowly cleared by CYP3A4 hydroxylation, then glucuronidation
How is bicalutamide excreted?
Parent drug and metabolites excreted by faeces and urine
What are the adverse effects of bicalutamide?
- Hot flushes
- Nausea, vomiting
- Dec sexual desire/ability (may need to take note of if patient is still sexually active)
- Fatigue
- Constipation/diarrhoea
- Mild swelling of ankles, legs and/or feet
What are the contraindications for bicalutamide?
- Women and children
- Patients with known hypersensitivity reaction to bicalutamide or any of the excipients
