cancer drugs Flashcards
Tamoxifen drug
SERM (selective estrogen receptor modulator)
Endocrine-based drug
* Reach breast tissue cancer cells
* Penetrate cell
*Enter nucleus, estrogen receptor
tamoxifen MOA
1) Competitively blocks endogenous estrogen binding to estrogen receptor in target tissue
2) Tamoxifen-ER complex
3) Alters estrogen-responsive gene expression
4) Prevent cell activation, proliferation
* Estrogenic// anti-estrogenic effects
* Tissue specific effects
- Breast, uterus, ovaries
tamoxifen structure
CIS: Estrogenic (normal estrogen effect)
TRANS: anti-estrogenic activity (block)
PK of tamoxifen
A: given orally. F~100%, rapidly, extensively absorbed in intestine
* Peak 5/ 3-7hrs
* Css reached after 3-4 wks, or ~16wks
D: plasma protein (albumin) binding >98%
* Vd: 50-60l/kg
○ High conc in breast, uterus, ovary, liver, kidney, lung, pancreas
§ Breast: 10x > circ
§ Uterus: 2-3x> circ
M: CL 1.4 ml.min^-1. Kg^-1
t1/2 = 5-7 days (tamoxifen)
E:
○ Mainly eliminated in feces
<1% urine excretion
metabolic pathways for tamoxifen
- Phase 1: hydroxylation, N-oxidation, dealkylation (break down)
- Major pathway = N-demethylation
○ Catalysed by CYP3A4 —> N-desmethyltamoxifen —> CYP2D6 —> endoxifen
○ Major metabolite: N-desmethyltamoxifen (t1/2 14 days)○ tamoxifen (cyp2d6) --> 4-OH tamoxifen --> (cyp3a4) ENDOXIFEN § Minor metabolites § Exhibit affinity for ER > tamoxifen - Phase 2: glucuronidation, sulphation
○ Add large hydrophilic molecules
active metabolites effect
4-OH tamoxifen & endoxifen
compete for ER with tamoxifen
greater affinity than tamoxifen, reduce therapeutic effects
potential tamoxifen DDI
CYP3A4: grapefruit
CYP2D6: diphenhydramine (cough, cold)
tamoxifen indicated for
- Breast cancer (early/ metastatic)
- Pre/ post menopausal
- Chemoprevention in women w/ high risk
- Family hist
- Genetic predisposition
- Reduce severity of osteoporosis (good SE, but not main indication)
- Other agents with better SE profile
SE of tamoxifen
- Hot flashes
- High risk of endometrial cancer
○ Cis isomers accumulate in ovaries, uterus
○ Regular monitoring required
§ Menstrual irregularities
§ Vaginal bleeding and discharge - Venous thromboembolic events (DVT)
- NV
Toxicity:
* High doses, lead to acute nephrotoxicity
○ Tremor, hyperreflexia, unsteady gait, dizziness
* Pt experience overdose: given supportive treatment
○ No specific treatment
Pembrolizumab drug
durable immune effects
T cell immunotherapy (immune checkpt inhibitors) is a PD1 blockers
1. PDL1- (cancer cell) i. competes with PDL1 receptor ii. No longer shield, stop growth 2. So t cell receptors PD1 receptor can bind and attack
MOA of Pembrolizumab
- Death receptor (PD-1) on T cell
- Pembrolizumab is PD-1 blocker, binds to T cell PD-1 receptor
- Allow release of PD-1 pathway-mediated T cell activities
- Prevent PDL1 ligand on cancer to inhibit T cell mediated immune response
structure of pembrolizumab
- Humanised Ab (90%)
○ Recombinant from CHO cells
○ Inhibit cancer metastasis
○Only the CDR is chimeric
○ CDR: hypervariable region of Ig - bind epitope
responsible for antigen specificity and affinity of AB
replace all but hypervariable CDR domains
PK of pembrolizumab
A: administered parenterally IV
* IV 200mg, every 3 wks
D: Vd small, ~7L
* Limited extravascular distribution
* Not bind to plasma proteins in specific manner
* Stay in circ
M: cleared from circ in non-specific catabolism
○ No metabolic drug interactions
* T1/2: 27 days, may reach Css after 19 wks
Affect CL:
1. Albumin (protein) and bilirubin lvl
2. Type of cancer
3. Gender (lower CL F>M)
a. Affects dosing
E: limited study on elimination route
non-specific catabolism
- Break down large mole into smaller units
- –> small peptides, aa by protein degradation
○ No metabolic drug interactions
- –> small peptides, aa by protein degradation
ADR of pembrolizumab
- Infusion-related SE (hypersensitivity to drug and components)
○ Rash
○ Itchiness - Fatigue
- Diarrhea
- Nausea
- Joint pain
- Life-threatening immune-related inflammation
○ Lung, endocrine organs, liver, kidney, sepsis
CI of pembrolizumab
- Pt on CS/ immunosuppressants
○ Must be stopped before taking pembrolizumab <– immune related inflammation
§ Then add back CS afterwards
○ Interfere with ADR - Pregnant women – miscarriage
- History of severe reactions:
○ Hypersensitivity to other biologics
○ other illnesses (infection, liver/ kidney disease)
prostate cancer signs and sx
- Difficulty urinating
- Low stream of urine
- Freq urination at night (affect QOL)
- Constant need to urinate
- Dark red urine
- Weak, swollen lower limbs
- Back pain
prostate growth depends on androgens.
androgen deprivation, reduce progression of prostate cancer.
ways to achieve androgen deprivation?
1) Inhibit pituitary gonadotropin release (GnRH)
Leuprorelin, leuprolide
2) Inhibit androgen synthesis
Finasteride
3) Inhibit androgen binding – androgen receptor blockers
flutamide, Bicalutamide
4) Surgical extirpation of glands: castration, adrenalectomy (remove 1-2 testicles to reduce testosterone)
Leuprorelin drug
Targets upstream GnRH agonists
MOA of leuprorelin
1) Continuous administration, constant GnRH release into pituitary gland
2) Suppress FSH, LH release
3) Decr androgens synthesis (testosterone release)
4) Minimise +ve stimulating effect on androgen sensitive prostate cancer cell
a) Cancer cell apoptosis
monitor for leuprorelin therapy
- prostate-specific antigens (PSA) in first few wks of therapy
○ Biomarker if prostate is hyperactive
○ Enlarged prostate? Benign prostatic hyperplasia? Cancer? - FSH, LH, serum testosterone after 4 wks therapy
May incr at start due to incr GnRH
structure of leuprorelin
Synthetic GnRH analogue
Acts as agonist at pituitary GnRH receptors
PK of leuprorelin
A: SC/ IM (single dose Long-Acting depot)
* 1,3,4 mnths interval
* Cmax: 1-3hrs post injection
* Css reached typically after 4wks
D: Vd ~27L after Iv
* No data on Vd after SC/ Im
* Display 45% plasma protein binding (in vitro) - not much data
M: degraded proteolytically by peptidases
* Into inactive peptides
○ Not metabolised in liver (CYP450)
* T1/2~ 3hr
E: <5% unchanged in urine
ADR of leuprorelin
- Local pain at inj site (~10% cases)
- Flushes
- Headaches/ migraine
- GI disturbances
- Altered mood
- Hyperglycemia
- Hyperlipidemia
*Loss of libido, impotency
CI of leuprorelin
- Hypersensitivity to Leuprorelin. Other GnRh agonist
- Pre-exist heart disease
- Pt risk of osteoporosis
- Incr fall risk due to low bone density
Bicalutamide drug
Direct blockade of hormone acting on its receptor
Androgen receptor ANTAGONIST
** not for monotherapy
** combi w/ GnRH analogue (alleviate symptoms of testosterone surge in GnRH agonists)
fast onset, relieve sx
MOA of bicalutamide
1) Blocks AR, inhibit action of androgens
- Competitive antagonise androgen receptor
- Inhibit nuclear translocation of AR
-Inhibit interaction of AR with promoter at AR response element
2) Inhibition of AR-dependent transcription
- Impairs cell proliferation
- Trigger apoptosis in cancer cells
3) Decr androgen, prevents prostate growth
- Decr progression of prostate cancer
4) Incr LH secretion/ FSH –> stimulate body to incr serum testosterone levels (undesirable outcome, when monotherapy)
structure of bicalutamide
Chiral centre, forms R/S isomers
structure of bicalutamide relating to its metabolism
Chiral centre, forms R/S isomers
- (S) -bicalutamide
○ Inactive alr, goes to phase 2
○ Glucuronidation - (R)- bicalutamide
○ Active, goes phase 1 –> 2
○ P1: Hydroxylation (CYP3A4)
○ P2: Glucuronidation
PK of bicalutamide
A: OD PO tablet
* Conjunction with GnRH analogue
D: highly plasma protein bound (albumin)
M: liver, stereoselective
* (S) -bicalutamide
○ Inactive alr, goes to phase 2
○ Glucuronidation
* (R)- bicalutamide ○ Active, goes phase 1 --> 2 ○ P1: Hydroxylation (CYP3A4) ○ P2: Glucuronidation * T1/2 ~ 6 days
E: bile, urine
ADR of bicalutamide
- Gynecomastia
- Sexual dysfunction
- Fatigue
- GI disturbances
- Seizures (rare)
bicalutamide indicated when
- Prostate cancer
- Androgen deprivation therapy
- Locally advanced disease
In conjunction To incr survival
* with radiation therapy
* With surgery
