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PR3152 Pharmacology > Endocrine cancers > Flashcards

Endocrine cancers Flashcards

1
Q

What is the MOA of Tamoxifen?

A

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

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2
Q

Does Tamoxifen have isomers? What do the different isomers mean?

A

Tamoxifen exists in cis- and trans- stereoisomers

cis-isomer : estrogenic activity
trans-isomer: anti-estrogenic activity

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3
Q

Describe the absorption properties of Tamoxifen

A

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

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4
Q

Describe the distribution of Tamoxifen

A

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.

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5
Q

How is Tamoxifen metabolised and eliminated?

A

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

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6
Q

What are the clinical uses of Tamoxifen?

A

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)

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7
Q

What are the side effects of Tamoxifen?

A

Hot flashes
↑ risk of endometrial cancer
Venous thromboembolic events (DVT)
Menstrual irregularities
Vaginal bleeding and discharge
Nausea, vomiting

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8
Q

How can Tamoxifen be potentially toxic?

A

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.

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9
Q

What is the MOA of Pembrolizumab?

A

A Programme-Death receptor-1 (PD-1) blocker,
which binds to PD-1 and releasing PD-1 pathway-
mediated inhibition of T-cell activities.

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10
Q

What type of antibody is Pembrolizumab?

A

Humanised Ab, chimera (from mouse)

Recombinantly manufactured from Chinese Hamster Ovary (CHO) cells

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11
Q

How is Pembrolizumab administered?

A

Administered slowing parenterally (IV infusion over 30min)

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12
Q

Describe the PK properties of Pembrolizumab.

A

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 )

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13
Q

What are the side effects of Pembrolizumab?

A

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.

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14
Q

What are the contraindications of Pembrolizumab?

A

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.

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15
Q

What are the 4 ways to achieve androgen deprivation?

A
  1. Inhibition of pituitary gonadotropin release: GnRH analogs (eg. Leuprorelin/Leuprolide)
  2. Inhibition of androgen synthesis (eg. Finasteride)
  3. Inhibition of androgen binding: androgen receptor blockers (eg. Flutamide)
  4. Surgical extirpation of the glands: castration and adrenalectomy
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16
Q

What are the pharmacologica strategies to treat prostate cancer?

A
  1. Target the upstream pathway/trigger
  2. Direct blockade of hormone acting
    on its receptor
17
Q

What is Leuprorelin (Leuprolide)?

A

Synthetic gonadotropin releasing hormone
(GnRH) analogue acting as an agonist at pituitary GnRH receptors

18
Q

How does Leuprorelin work for prostate cancer?

A

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

19
Q

How to monitor the effectiveness of the treatment for prostate cancer?

A

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

20
Q

Describe the PK properties of Leuprolide.

A

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

21
Q

What are the side effects of Leuprorelin?

A
  • Local pain & redness @ injection site (~10% cases)
  • Hot flushes during first few weeks of Tx
  • Headaches/dizziness
  • GI disturbances
  • Altered mood
  • Hyperglycemia
  • Decreased libido
22
Q

What are the contraindications of Leuprorelin?

A
  • Hypersensitivities to Leuprorelin or other GnRH agonists
  • Pre-existing heart disease
  • Patients with risks for osteoporosis
23
Q

What is Bicalutamide?

A

Androgen Receptor (AR) antagonist (antiandrogen)

24
Q

Should Bicalutamide be used as monotherapy in prostate cancer?

A

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

25
Q

What is the MoA of Bicalutamide?

A
  • 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
26
Q

What are the clinical uses of Bicalutamide?

A
  • 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)
27
Q

Describe the PK properties of Bicalutamide.

A

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

28
Q

What are the side effects of Bicalutamide?

A
  • Hot flushes
  • Nausea/vomiting
  • ↓ Sexual desire/ability
  • Fatigue
  • Constipation/diarrhea
  • Mild swelling ankles/legs/feet
29
Q

What are the contraindications of Bicalutamide?

A
  • Women and children
  • Patients with known hypersensitivity reaction
    to bicalutamide or to any excipients of this product

PR3152 Pharmacology (3 decks)

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