Endocrine cancers Flashcards
What is the MOA of Tamoxifen?
Selective estrogen receptor (ER) modulator
(SERM)
Competitively blocks endogenous estrogen
binding to the estrogen receptor in the
target tissue (eg. breast) –> tamoxifen-ER
complex alters estrogen-responsive gene
expression –> preventing cell activation
and proliferation
Does Tamoxifen have isomers? What do the different isomers mean?
Tamoxifen exists in cis- and trans- stereoisomers
cis-isomer : estrogenic activity
trans-isomer: anti-estrogenic activity
Describe the absorption properties of Tamoxifen
Given orally
Rapidly and extensively absorbed in intestine
F ~ 100%
Peak time 5 (3-7)hrs
Css reached typically after 3-4 weeks and may possible up to 16 weeks
Describe the distribution of Tamoxifen
Plasma protein (albumin) binding >98%
Vd 50-60 L/kg
Reason: High concentrations of tamoxifen have been found in breast, uterus, liver, kidney, lung, pancreas, and ovary tissue in humans.
Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation and in the breasts 10-fold higher than in the circulation.
How is Tamoxifen metabolised and eliminated?
M: CL 1.4 ml.min-1.kg-1
Elimination T1/2 5-7 days (tamoxifen)
Phase 1: Hydroxylation, N-oxidation, dealkylation
Phase 2: Glucuronidation, sulphation
Major pathway of metabolism = N-demethylation (catalyzed by CYP3A)
One of the major metabolites: N-desmethyltamoxifen (T1/2 ~14 days)
Has active metabolites by CYP2D6 (4-hydroxytamoxifen &
4-hydroxy-N-desmethyltamoxifen (endoxifen) are minor
metabolites that exhibit affinity for the oestrogen receptor
that is greater than that of tamoxifen)
E: Mainly eliminated in feces, negligible (<1%) urinary excretion
What are the clinical uses of Tamoxifen?
Breast cancer (early and metastatic)
Both pre- and post-menopausal women
May be useful in chemoprevention of breast cancer in women @ high risk
Reduces the severity of osteoporosis (but not used for that indication because
of the availability of agents with superior side effect profiles)
What are the side effects of Tamoxifen?
Hot flashes
↑ risk of endometrial cancer
Venous thromboembolic events (DVT)
Menstrual irregularities
Vaginal bleeding and discharge
Nausea, vomiting
How can Tamoxifen be potentially toxic?
High doses could lead to acute neurotoxicity
(tremor, hyperreflexia, unsteady gait,
dizziness.
Patients experiencing an overdose should be
given support treatment; no specific
treatment for overdose is suggested.
What is the MOA of Pembrolizumab?
A Programme-Death receptor-1 (PD-1) blocker,
which binds to PD-1 and releasing PD-1 pathway-
mediated inhibition of T-cell activities.
What type of antibody is Pembrolizumab?
Humanised Ab, chimera (from mouse)
Recombinantly manufactured from Chinese Hamster Ovary (CHO) cells
How is Pembrolizumab administered?
Administered slowing parenterally (IV infusion over 30min)
Describe the PK properties of Pembrolizumab.
Distribution: Vd small (~7L) with limited extravascular distribution
Metabolism: Pembrolizumab is cleared from the circulation through non-specific catabolism, no metabolic drug interactions are expected and no studies were done on routes of elimination.
T1/2 ~27 days; may reach Css after ~19 weeks
Factors influence clearance: types of cancer, gender (lower CL in females )
What are the side effects of Pembrolizumab?
Infusion-relation S/Es such as rash and itchiness
Fatigue
Diarrhoea
Nausea
Joint pain
(Life threatening) Immune-related inflammation on lung, endocrine organs,
liver, kidney, sepsis.
What are the contraindications of Pembrolizumab?
If a patient is taking corticosteroids or
immunosuppressants should be stopped before
starting pembrolizumab
[Reason: they may interfere with pembrolizumab]
- corticosteroids or immunosuppressants may be used after pembrolizumab is started to deal with immune-related adverse effects
Not to be administered to pregnant women…may
increase risk of miscarriage
Patients who have a history of severe reaction (eg. hypersensitivity) to another antibody therapy,
other illnesses (eg. infection, liver/kidney diseases etc) –> consult doctors.
What are the 4 ways to achieve androgen deprivation?
- Inhibition of pituitary gonadotropin release: GnRH analogs (eg. Leuprorelin/Leuprolide)
- Inhibition of androgen synthesis (eg. Finasteride)
- Inhibition of androgen binding: androgen receptor blockers (eg. Flutamide)
- Surgical extirpation of the glands: castration and adrenalectomy
What are the pharmacologica strategies to treat prostate cancer?
- Target the upstream pathway/trigger
- Direct blockade of hormone acting
on its receptor
What is Leuprorelin (Leuprolide)?
Synthetic gonadotropin releasing hormone
(GnRH) analogue acting as an agonist at pituitary GnRH receptors
How does Leuprorelin work for prostate cancer?
Decreased androgen (testosterone)
production in testes –> minimizes the (+)y effect on androgen-sensitive prostate cancer cell –> cancer cells undergo apoptosis
Continuous administration –> (-)s FSH and LH release –> suppress androgen
synthesis
How to monitor the effectiveness of the treatment for prostate cancer?
Measure:
Prostate-specific antigen (PSA) in first few weeks of therapy
Luteinizing hormone (LH), follicle-stimulating hormone (FSH)
levels and serum testosterone after 4 weeks of therapy
Describe the PK properties of Leuprolide.
A: SC or IM typically given as a single-dose long-acting depot: interval between injections may vary depending on the dose @ 1, 3 or 4 months interval, Cmax reached within 1 – 3hrs post-injection, Css reached typically after 4 weeks
D: Vd ~ 27L after IV
Displays ~45% plasma protein binding in vitro
M: degraded proteolytically (potentially by peptidases)
into inactive peptides
T1/2 ~3hr (a single D-amino acid (D-leucyl) residue helps to increase its circulating T1/2 from 3-4min to 3hrs)
Not metabolized in liver CYP 450
E: <5% via urine
What are the side effects of Leuprorelin?
- Local pain & redness @ injection site (~10% cases)
- Hot flushes during first few weeks of Tx
- Headaches/dizziness
- GI disturbances
- Altered mood
- Hyperglycemia
- Decreased libido
What are the contraindications of Leuprorelin?
- Hypersensitivities to Leuprorelin or other GnRH agonists
- Pre-existing heart disease
- Patients with risks for osteoporosis
What is Bicalutamide?
Androgen Receptor (AR) antagonist (antiandrogen)
Should Bicalutamide be used as monotherapy in prostate cancer?
Should not be used in monotherapy of prostate
cancer
Reason: Blocks AR –> ↑LH secretion –> (+) higher
serum testosterone levels
To be used primarily in conjunction with GnRH
analogue to alleviate the effects of testosterone
surge (tumor flare) that occurs with a GnRH agonist
in the treatment of metastatic prostate cancer
What is the MoA of Bicalutamide?
- Anti-androgen
- Acts competitively to antagonize 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 ↓ progression of
prostate cancer
What are the clinical uses of Bicalutamide?
- Prostate cancer
- Androgen deprivation therapy (used during the initiation of androgen deprivation therapy with a LHRH agonist to reduce the symptoms of tumor flare in patients with
metastatic prostate cancer) - For locally advanced disease (in conjunction with radiation therapy or surgery –> ↑ survival)
Describe the PK properties of Bicalutamide.
A: well absorbed orally; food does not affect bioavailability orally once daily dose in conjunction with a GnRH analogue
D: highly plasma protein bound (racemic 96%; (R)-bicalutamide >99%)
M: extensively metabolized in Liver
racemic; Stereoselective
(S)-bicalutamide [inactive] – rapidly cleared by glucuronidation
(R)-Bicalutamide [active] – slowly hydroxylation (CYP 3A4) –> glucuronidation
T1/2 ~ 6 days [(R)-bicalutamide]
E: parent drug & metabolites
via bile and urine
What are the side effects of Bicalutamide?
- Hot flushes
- Nausea/vomiting
- ↓ Sexual desire/ability
- Fatigue
- Constipation/diarrhea
- Mild swelling ankles/legs/feet
What are the contraindications of Bicalutamide?
- Women and children
- Patients with known hypersensitivity reaction
to bicalutamide or to any excipients of this product
