PR3152 IC10 Flashcards
what is the mechanism of action of tamoxifen
SERM = selective estrogen receptor modulator
it prevents binding of endogenous estrogen to the estrogen receptor by forming tamoxifen-ER complex = alter gene expression = prevent cell activation and proliferation
isomerism of tamoxifen?
it exists as cis trans stereoisomer
cis isomer = estrogenic activity
trans isomer = anti-estrogenic activity
absorption of tamoxifen
BA, peak, Css
oral
~100% bioavailability
peak 5hours
takes 3-4 weeks for Css (up to 16 weeks)
distribution of tamoxifen
percentage binding, Vd
> 98% plasma protein binding
high Vd 50-60L/kg
multi organ involvement
concentrates at the uterus and breast (10fold)
metabolism of tamoxifen
CL, t1/2, enzymes
CL 1.4ml/min/kg
t1/2 5-7 days
phase 1: hydroxylation, n-oxidation, dealkylation
phase 2: glucoronidation, sulphation
major pathway = n-demethylation primarily by CYP3A4 = N-desmethyltamoxifen
half life of N-demethyltamoxifen
14 days
what is the other metabolism route for tamoxifen (NAME the CYP)
cyp2D6
4-oh-tamoxifen and 4-oh-desmethyltamoxifen
minor metabolites
exhibit strong affinity to the estrogen receptors
specific counselling points for tamoxifen (food/drug)
GRAPEFRUIT JUICE : 3A4 INHIBITOR
SSRI, antidepressants: 2D6 inhibitor
diphenhydramine is a 2c6 inhibitor
clinical uses of tamoxifen
breast cancer (early and metastatic)
both pre and post menopausal women
may be useful in chemoprevention of breast cancer in high risk women
side benefit of reducing osteoporosis risk
side effects of tamoxifen
Lower estrogen = hot flashes similar to menopause:
* Hot flashes
Acting on the estrogen receptor in the uterus, similar to COCs:
* ↑ risk of endometrial cancer
* Venous thromboembolic events (DVT)
* Menstrual irregularities
* Vaginal bleeding and discharge
Others:
* Nausea, vomiting
toxicity of tamoxifen?
- 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.
excretion of tamoxifen
mainly fecal
negligible urine excretion (<1%)
mechanism of action of pembrolizumab
bind to PD1 receptor on T cells to prevent activation of PD1 pathway mediated inhibition of T cell activities
- prevents binding of PDL1 expressed by tumor cells to evade immune respnose from T-cells
inhibits cancer metastasis (for cervical cancer)
PD1 receptor BLOCKERS
what is the ADME of prembrolizumab?
t1/2
css
vd
A: nil
D: poor Vd (~7), low extravascular circulation
M: by non specific catabolism
t1/2 = ~27 days, Css after 19 weeks
E: unknown
what is the dosing instructions for pembrolizumab?
200mg IV over 30 min x every 3 week
factors influencing clearance of pembrolizumab
gender (female lower CL)
type of cancer
side effects of pembrolizumab
- Infusion-relation S/Es such as
Rash, itchiness - Fatigue
- Diarrhoea
- Nausea
- Joint pain
- (Life threatening) Immune-related inflammation on lung, endocrine organs, liver, kidney, sepsis.
contraindications of pembrolizumab
X corticosteroids
X pregnancy (increase miscarriage risk)
X history of severe reaction to another antibody therapy
X illnesses e.g., infection, liver/kidney disease etc.
mechanism of action of leuprorelin
GnRH analogue = agonist at the pituitary GnRH receptors = continuous administration = inhibit LH and FSH = suppress androgen production at testes = inhibits stimulatory effect on prostate cancer cells = apoptosis
monitoring after leuprorelin administration
1) prostate specific antigen in the first few weeks
2) LH, FSH, serum testosterone after 4 weeks .
absorption of leuprorelin
PEAK CSS
SC IM dosing interval 1,3,4 weeks depending on the dose
peak = 1-3hours
Css = ~4 weeks
distribution of leuprorelin
vd
ppm
Vd for IV = 27L/kg
not known for IM SC
plasma protein binding ~45% in vitro
metabolism of leuprorelin
t1/2
by proteolysis
t1/2 = 3 hours due to a single D isomer of leucyl residue that increases t1/2 from 3-4 min
not metabolised by liver cyp450
excretion of leuprorelin
<5% excreted via urine
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
contraindications of leuprorelin
- Hypersensitivities to Leuprorelin or other GnRH agonists
- Pre-existing heart disease
- Patients with risks for osteoporosis
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.
Used in conjunction with GnRH agonists at initiation to reduce effects of serum testosterone surge (tumour flare)
Prostate growth req androgens, so androgen dep ↓ prog of prostate cancer
clinical use of bicalutamide
Prostate cancer
For locally advanced disease (in conjunction with radiation therapy or surgery = ↑survival)
absorption of bicalutamide
well absorbed orally
oral dose once daily with GnRH agonist
distribution of bicalutamide
protein binding
highly plasma protein bound (racemic 96%; (R)-bicalutamide >99%)
metabolism of bicalutamide
t1/2
extensively metabolized in Liver
Racemic; Stereoselective
(S)-bicalutamide [inactive]: rapidly cleared by glucuronidation
(R)-Bicalutamide [active]: slow hydroxylation (CYP 3A4) = glucuronidation
t1/2 6 hours for R-bicalutamide
elimination of bicalutamide
parent drug & metabolites via bile and urine
side effects of bicalutamide
- Hot flushes
- N/V/D
- ↓libido
- Fatigue
- Constipation
- Mild swelling ankles/legs/feet
contraindications of bicalutamide
women and children
known hypersensitivity to bicalutamide or any excipients
