IC9 Pharmacology of Endocrine Cancer Drugs Flashcards
What is tamoxifen and its MOA?
Selective estrogen receptor modulator (SERM)
Competitively inhibits estrogen from binding to estrogen receptor (present in breast, uterus, kidney, lung, pancreas, ovary)
- Partial blocking
- Cis isomer (agonist)
- Trans isomer (antagonist)
alters estrogen-responsive gene expression
prevents cell activation and proliferation
What is the PK of tamoxifen?
A: oral (1-4 months to reach Css), rapid absorption
D: highly distributed, highly plasma protein bound
M: Phase 1 and Phase 2 metabolism
- CYP3A4 –> N-desmethyl-tamoxifen –> CYP2D6 –> 4-hydroxy-N-desmethyl-tamoxifen (ACTIVE)
OR
- CYP2D6 –> 4-hydroxy-tamoxifen –> CYP3A4 –> 4-hydroxy-N-desmethyl-tamoxifen (ACTIVE)
- Endoxifen (4hNd, most active metabolite) has higher affinity for estrogen receptors than tamoxifen
E: feces
What are the ADRs of tamoxifen?
Think of cis isomer (activating the estrogen receptor)
- Hot flushes
- Endometrial cancer
- Venous Thromboembolism (VTE)
- (HIGH DOSES) acute neurotoxicity –> tremor, hyperreflexia, unsteady gait, dizziness [should be given support treatment]
What is tamoxifen used for?
- Breast Cancer (treatment and chemoprevention)
- Pre- or post-menopausal women
- Reduce severity of osteoporosis (but NOT indicated)
What are the special considerations of tamoxifen?
DDI:
1. Grapefruit (CYP3A4 inhibitor)
2. Diphenhydramine, antidepressants (CYP2D6 inhibitor)
What is pembrolizumab and its MOA?
PD-1 inhibitor
- Binds to PD-1 found on T cells, prevent PD-1 from binding to PD-L1 on cancer cells, prevent “hiding” of cancer cells
- Inhibits cancer metastasis
Humanized Ab
Created by CHO cells
What is the PK of pembrolizumab?
A: IV
D: minimal distribution (due to large MW), NOT plasma protein bound, very long t1/2
M: non-specific, proteolysis via general protein degradation
Factors influencing clearance:
- albumin and bilirubin levels
- type of cancer
- lower CL in females
E: -
What are the ADRs of pembrolizumab?
- Injection site reaction (rash, itchiness, irritation)
- Hypersensitivity issue to API and excipients
- (fatal) Immune related inflammation on lung, endocrine organs, liver, kidney, sepsis –> it’s an immunomodulator
What is pembrolizumab used for?
Cervical cancer
What are the special considerations of pembrolizumab?
- Consult dr if patients have hypersensitivity issues to antibody therapy / have other illnesses e.g. infection, liver/kidney diseases
CI:
- Contraindicated in pregnancy (increased risk of miscarriages)
DDI:
- Avoid taking corticosteroids with pembrolizumab
- stop it before starting pembrolizumab
- take after started on pembrolizumab to tackle immune-related ADR
What is leuprorelin/leuprolide and its MOA? What to monitor for?
GnRHR agonist / synthetic GnRH analogue
–> act on pituitary GnRH receptors
- Continuous administration (too much thus negative feedback) –> decrease FSH and LH
–> suppress androgen synthesis in testes - –> minimize positive effect on androgen-sensitive prostate cancer cells
- –> cancer cells undergo apoptosis (not fed with androgen)
Monitor:
- Prostate specific antigen (PSA)
o The higher PSA is, the worse the prostate cancer - LH, FSH and testosterone levels (after 4wks of therapy)
What is the PK of leuprorelin?
A: SC or IM (long depot)
D: -
M: degraded proteolytically (potentially by peptidases) into inactive peptides, NOT metabolized in liver CYP450
E: urine (mostly excreted metabolized)
What are the ADRs of leuprorelin?
- Injection site reaction
- Flushes
- Headache/migraine
- GI
- Altered mood
- Hyperglycemia
- hyperlipidemia
- Loss of libido, impotence (due to reduced testosterone)
What is leuprorelin used for?
Prostate Cancer
What are the special considerations for leuprorelin?
CI:
1. Hypersensitivities to GnRH agonists
2. Pre-existing heart disease
3. Patients w osteoporosis risk
