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
