Endocrine Cancers Flashcards
What drug is used in breast cancer?
Tamoxifen (oral tablet)
Describe Tamoxifen MOA
Selective estrogen receptor modulator (SERM)
*Anti-estrogenic
Competitively blocks endogenous estrogen binding to the ER in the target tissue (breast)
Form Tamoxifen-ER complex that alters estrogen-responsive gene expression (inactivates transcription)
Prevent cell activation and proliferation
*Cancer cells use estrogen hormone to grow, hence block estrogen binding to the ER to slow cancer growth
Explain why Tamoxifen exhibits both estrogenic and anti-estrogenic effect
*Alkene group in the structure
Cis-isomer: estrogenic activity
Trans-isomer: anti-estrogenic activity
List the clinical uses of Tamoxifen
- Breast cancer (in both pre and post menopausal women)
- Chemoprevention of breast cancer in women at high risk (e.g., FH, genetic predisposition)
- (NOT USED FOR THIS INDICATION) Reduce severity of osteoporosis - estrogen regulates bone density
Describe the absorption profile of Tamoxifen
Rapidly absorbed in intestine, bioavailability of 100%
Takes 3-4 weeks (up to 16 weeks) to reach steady tate
Describe the distribution profile of Tamoxifen
Plasma protein binding >98%
High Vd 50-60L/kg
Tamoxifen concentrates in breast, uterus, liver, kidney, lung, pancreas, ovary tissues
Describe the metabolism profile of Tamoxifen
Phase 1: Hydroxylation, N-oxidation, dealkylation
Phase 2: Glucoronidation, sulphation
Major pathway: N-demethylation (catalysed by CYP3A4) => N-desmethyl-tamoxifen
*N-desmethyl-tamoxifen can be metabolised via CYP2D6 to Endoxifen
Alternative: CYP2D6 => 4-OH tamoxifen => CYP3A4 => Endoxifen
*Endoxifen is also known as 4-hydroxy-N-desmethyltamoxifen
Which metabolites of Tamoxifen have estrogenic activity as well
CYP2D6 metabolites: 4-OH Tamoxifen and Endoxifen (4-hydroxy-N-desmthyltamoxifen)
These minor metabolites exhibit greater affinity for the ER than Tamoxifen
What are some DDI or FDI that can occur with Tamoxifen?
Grapefruit juice: inhibits CYP3A4
Diphenhydramine: inhibits CYP2D6
=> Incr Tamoxifen levels
Describe the elimination profile of Tamoxifen
Eliminated mainly via feces
What are some SEs of Tamoxifen?
- Hot flushes - think low levels of estrogen (menopausal effects)
- Incr risk of endometrial (uterus) cancer - think accumulation of cis isomer
- Venous thromboembolic events (DVT)
- Menstrual irregularities - early sign of endometrial cancer
- Vaginal bleeding and discharge - early sign of endometrial cancer
- Nausea, vomiting
What are some toxicity issues with high doses of Tamoxifen?
High doses => acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness)
*Overdose - supportive treatment (no antidote)
What drug is used in cervical cancer?
Pembrolizumab (biologic) - IV, parenteral
What is the MOA of Pembrolizumab?
Checkpoint inhibitor (PD-1 blocker)
Binds to PD-1 on T cells, prevent binding of PD-L1 on cancer cells to PD-1, therefore prevent PD-1 pathway-mediated inhibition of T-cell activities
=> basically T cell can now kill the cancer cell
Inhibit cancer metastasis
How is Pembrolizumab manufactured?
Humanized antibody
- recombinantly manufactured from CHO cells
Describe Pembrolizumab absorption profile
Parenteral (IV)
200mg IV, every 3 weeks (may last longer than >8months)
Css after 19 weeks
Describe Pembrolizumab distribution profile
Small Vd 7L
Limited extravascular distribution (mostly limited to blood circulation)
Not expected to bind to plasma protein in a specific manner
Describe the metabolism of Pembrolizumab
Non-specific catabolism (general protein degradation of large mAb into small peptides and AAs)
E.g., lysosomal degradation, proteasomal degradation
What are some factors affecting the clearance of Pembrolizumab
Gender - clearance lower in females
Albumin (plasma protein) levels, bilirubin levels
Types of cancer
What are the SEs of Pembrolizumab?
- Infusion-related SE: rash, itchiness, hypersensitivity to drug components
- Fatigue
- Diarrhea
- Nausea
- Joint pain
- Life-threatening immune related inflammation of lungs, endocrine organs, liver, kidney
- Sepsis
What are the contraindications of Pembrolizumab?
Corticosteroids and Immunosuppressants
- Stop before starting Pembrolizumab as immunosuppressive effects may interfere with action of Pembrolizumab
- May be used after Pembrolizumab to deal with immune-related adverse events
Pregnant women
- incr risk of miscarriage
History of severe reaction (hypersensitivity) to other antibody therapy
Patients with other illnesses (infections, liver/kidney disease) => consult doctor
What are the signs and symptoms of prostate cancer?
- Difficulty urinating
- Low stream of urine
- Frequent urination at night
- Constant need to urinate
- Dark reddish urine
- Weak or swollen lower limb
- Back pain
What are the 4 methods used to treat prostate cancer?
*Androgen (testosterone) deprivation - as androgen promotes growth of normal and cancerous prostate cells by binding to and activating the androgen receptor on prostate cells
- GnRH analogs (Leuprorelin/Leuprolide)
- Inhibit pituitary gonadotropin (LSH/FH) release
- 5-alpha reductase inhibitor (Finasteride)
- Inhibit androgen synthesis (prevent testosterone to DHT)
- Androgen receptor blockers (Flutamide, Bicalutamide)
- Inhibit androgen binding to androgen receptor
- Surgical extirpation of the glands (Castration, adrenalectomy, orchiectomy)
- remove testes to reduce testosterone levels
Describe the MOA of Leuprorelin (SC/IM)
Synthetic gonadotropin releasing hormone (GnRH) analogue, acts as agonist at pituitary GnRH receptor (in CNS)
Continuous administration of GnRH agonist cause desensitization of GnRH receptor, leading to decrease LH and FSH release, and thus suppression of androgen synthesis
(*recall that normal circumstance: intermittent GnRH release in pulses)
*Decrease androgen => dcr growth and proliferation of androgen-sensitive prostate cancer cells => apoptosis => decrease progression of prostate cancer
What are the monitoring parameters for Leuprorelin treatment
- PSA (prostate-specific antigen): higher PSA means enlarged prostate
=> should decrease in first few weeks of therapy - LH, FSH, serum testosterone levels (after 4 weeks of therapy)
Describe the absorption profile of Leuprorelin
SC/IM given as single dose long-acting depot @ 1, 3, or 4 months interval
Cmax 1-3h post injection
Css after 4 weeks
Describe the distribution profile of Leuprorelin
45% plasma protein binding in vitro
Vd 27L after IV (no info on SC or IM)
Describe the metabolism of Leuprorelin
It is a polypeptide, degraded proteolytically (potentially by peptidases)
Describe the elimination of Leuprorelin
<5% excreted unchanged via urine
What are the SEs of Leuprorelin?
- Local pain at injection site
- Flushes
- Headache/migraine
- GI disturbances
- Altered mood
- Hyperglycemia
- Hyperlipidemia
- Loss of libido, impotence
What are the contraindications with Leuprorelin?
- Hypersensitivities to Leuprorelin or other GnRH agonists
- Preexisting heart disease
- Pt at risk for osteoporosis
What is the MOA of Bicalutamide?
Androgen receptor antagonist
Competitively antagonizes the AR
- Inhibit nuclear translocation of the AR from cytoplasm into nucleus
- Inhibit interaction of AR with AR response element in the nucleus
- Inhibit AR-dependent transcription
- Impair cell proliferation and trigger apoptosis in cancer cells
*Decrease androgen => dcr growth and proliferation of androgen-sensitive prostate cancer cells => apoptosis => decrease progression of prostate cancer
Why is Bicalutamide not used as monotherapy for prostate cancer?
Blocks AR => incr LH secretion (due to negative feedback) => higher serum testosterone levels
*Initial surge in LH and testosterone
*NOT used as monotherapy for prostate cancer - use with GnRH analogue
=> alleviate effects of testosterone surge
What are the clinical uses of Bicalutamide?
- Prostate cancer
- Androgen deprivation therapy
- Locally advanced disease - advanced stage of prostate cancer (in conjunction with radiation therapy or surgery, to increase survival)
Describe the absorption of Bicalutamide
Oral, once daily in combi with GnRH analogue
Describe the distribution of Bicalutamide
Highly plasma protein bound (albumin)
Describe the metabolism of Bicalutamide
*Take note of stereoisomers
Metabolised in the liver
Stereoselective (due to chiral center)
- S-bicalutamide (inactive): phase 2 glucuronidation
- R-bicalutamide (active): phase 1 hydroxylation via CYP3A4, phase 2 glucuronidation
Describe the elimination of Bicalutamide
Eliminated in bile and urine
What are the SEs of bicalutamide?
- Gynecomastia
- Sexual dysfunction
- Fatigue
- GI disturbances
- Seizure (rare)
