IC10 PK of drugs for endocrine cancers

Question 1

tamoxifen drug type

Answer 1

Selective oestrogen receptor modulator

Question 2

tamoxifen MOA

Answer 2

Completely blocks endogenous oestrogen binding in target tissue [breast]

• tamoxifen-ER complex alters oestrogen-responsive gene expression
  (Enters nucleus & bind to DNA)
• Prevention of cell activation & proliferation
  (Suppressing cell division & proliferation of proteins & signals)

Question 3

tamoxifen PK
Absorption

administration, F, peak conc, Css

Answer 3

• PO tablets
• Rapidly & extensively absorbed in intestines (F = ~100%)
• Peak time: 5 hours (within range of 3-7 hours)
• Css reached typically after 3-4 weeks; may be possible up to 16 weeks

Question 4

tamoxifen PK
distribution

plasma protein binding, Vd, concentration in tissues

Answer 4

Plasma protein binding > 98%

Vd: 50-60 L/kg (large)

High concentrations of tamoxifen found in breast, uterus, liver, kidney, lung, pancreas & ovary tissue
* Greater selectivity in breast & uterus ⇒ exert anti-estrogenic & anti-cancer effects

Question 5

tamoxifen PK
metabolism - t1/2

Answer 5

5-7 days

Question 6

tamoxifen PK
metabolism - phases

Answer 6

1: Hydroxylation, N-oxidation, dealkylation
2: Glucuronidation, sulphation

Question 7

tamoxifen PK
metabolism - pathways

Answer 7

Major: N-desmethyl tamoxifen by CYP3A4
* t1/2 ~14 days: takes longer time to reach Css

Minor: active metabolites by CYP2D6
* 4-hydroxytamoxifen & 4-hydroxy-N-desmethyltamoxifen (endoxifen)
* Exhibits affinity for oestrogen receptor; greater than tamoxifen
* CYP2D6 can be inhibited by diphenhydramine (impt to replace antihistamine choice)

Question 8

tamoxifen PK
metabolism - end product

Answer 8

endoxifen ⇒ most active metabolite

Question 9

tamoxifen PK
excretion

Negligible urinary

Answer 9

Mainly excreted in faeces (most metabolism in liver)
Negligible urinary excretion

Question 10

tamoxifen clinical uses

Answer 10

1. Breast cancer (early & metastatic)
2. Both pre- & post-menopausal women ⇒ regulation of oestrogen levels
3. May be useful in chemoprevention of breast cancer in women @ high risk
4. Reduces severity of osteoporosis
   * not used for that indication due to availability of agents with better SE profiles

Question 11

tamoxifen toxicity

Answer 11

High doses → acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness)
Patients experiencing overdose should be given support treatment

Question 12

tamoxifen SE

Answer 12

• Hot flashes → upper body (face, chest & neck) feeling warm
• ↑ risk of endometrial cancer
• Venous thromboembolic events (VTE): ie DVT
• Menstrual irregularities; vaginal bleeding & discharge
• Nausea, vomiting ⇒ common for anti-cancer drugs

Question 13

Pembrolizumab
role of PD1 receptors (normal)

Answer 13

Expressed by T cells → can detect cancer cells via cancer Ag expressed on tumour cell surface → T cell activation (immunity against cancer)

Question 14

Pembrolizumab
role of PD1 receptors (cancer)

Answer 14

Engagement with PD-L1 on cancer cell ⇒ inhibits T cell activation

Question 15

Pembrolizumab MOA

Answer 15

• Prevents PD-L1 expressed on cancer cells to interact with PD-1 ⇒ PD-L1 do not bind to PD-1
• Hence T cells still can be activated
• Releases PD-1 pathway-mediated inhibition of T cell activities
• Inhibits cancer metastasis

Question 16

Pembrolizumab
Formulation & dosage

Answer 16

Humanised Ab (from mouse) ⇒ have high affinity to PD-1 receptors
Recombinant; manufactured from CHO cells

Dose (adults): IV 200mg, every 3 weeks (IV infusion over 30 mins)
may last longer than 8 months → depends on severity of cancer

Question 17

Pembrolizumab PK
distribution

Vd

Answer 17

Small Vd (~7L; close to circulatory volume)
Limited extravascular distribution ⇒ mostly in plasma, lesser in tissues

Question 18

Pembrolizumab PK
Metabolism

Answer 18

Clearance from circulation through non-specific catabolism (breakdown to small amino acids by enzymes)

Question 19

Pembrolizumab PK
factors affecting CL

Answer 19

Types of cancer
Gender ⇒ lower in females

Question 20

Pembrolizumab SE

Answer 20

Infusion-relation: rash & itchiness
* Hypersensitivity to drug & components at site of injection

Fatigue, Joint pain
Diarrhoea, Nausea
(Life threatening) Immune-related inflammation on lung, endocrine organs, liver, kidney, sepsis.

Question 21

Pembrolizumab contraindications

Answer 21

1. Patients taking corticosteroids/ immunosuppressants
   Should stop before starting on pembrolizumab
   May interfere with pembrolizumab
   Can be used AFTER pembrolizumab → for immune-related AE
2. Pregnant women
   Increases risk of miscarriage
3. Patients with history of severe reaction (ie: hypersensitivity) to another antibody therapy OR have other illnesses (ie: infection, liver/kidney diseases)

Question 22

leuprorelin drug type

Answer 22

Synthetic gonadotropin releasing hormone (GnRH) → agonist at pituitary GnRH receptors

Question 23

leuprorelin MOA

Answer 23

• Constant stimulation of pituitary → reduces FSH & LH release ⇒ suppress androgen release (via negative feedback)
• Decreased androgen (testosterone) production in testes ⇒ minimises + effect on androgen-sensitive prostate cancer cell
• Cancer cell will undergo apoptosis

Question 24

leuprorelin monitoring

Answer 24

1. Prostate-specific antigen (PSA) in first few weeks of therapy
   Normal: <5 & Cancer: >10
   Generally shows decrease = effectiveness of treatment
2. LH, FSH levels & serum testosterone after 4 weeks of therapy

Question 25

leuprorelin PK absorption - route of administration

Answer 25

SC/ IM dosage forms → single-dose long-acting depot Slow release upon injection Possible IV infusion

Question 26

leuprorelin PK absorption - dosing interval

Answer 26

vary depending on dose at 1,3 or 4 months interval (depends on preparation)

Question 27

leuprorelin PK absorption - Cmax & Css

Answer 27

Cmax = within 1-3 hours Css = after 4 weeks

Question 28

leuprorelin PK distribution | Vd, plasma protein binding

Answer 28

Vd ~27L after IV ⇒ can distribute to tissues (prostate) No data on Vd after SC/ IM ~45% plasma protein binding

Question 29

leuprorelin PK Metabolism | how it occurs & t1/2

Answer 29

Polypeptide degraded proteolytically into inactive peptides Potentially by peptidases t1/2 ~ 3hrs due to Single D-amino acid (D-leucyl) residue

Question 30

leuprorelin PK excretion

Answer 30

<5% via urine

Question 31

leuprorelin SE | P&R, HF, L, H/D/AM, HG, GI

Answer 31

Local pain & redness @ injection site (~10% cases) Hot flushes during first few weeks of treatment Headaches/dizziness, altered mood GI disturbances Hyperglycemia decreased libido (due to lesser testosterone production)

Question 32

leuprorelin contraindications

Answer 32

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

Question 33

Bicalutamide drug type

Answer 33

Androgen receptor antagonist [anti-androgen]

Question 34

Bicalutamide reason for combination with GnRH agonist

Answer 34

(GnRH agonists) Initial stages: Blocks AR → ↑LH secretion → (+) higher serum testosterone levels Used primarily together with GnRH analogue ⇒ reduce effects of testosterone surge (tumour flare) that occurs with GnRH agonist in treatment of metastatic prostate cancer

Question 35

Bicalutamide MOA

Answer 35

Anti-androgen, acts competitively to antagonise androgen receptor 1. Inhibits nuclear translocation of AR + interaction of AR with promoter at AR response element * Inhibition of AR-dependent transcription → impairs cell proliferation ⇒ triggers apoptosis in cancer cells 2. Androgen deprivation ⇒ decreases progression of prostate cancer

Question 36

Bicalutamide clinical uses

Answer 36

1. Prostate cancer 2. Androgen deprivation therapy used during the initiation of androgen deprivation therapy with a LHRH agonist to reduce the symptoms of tumour flare in patients with metastatic prostate cancer 3. For locally advanced disease (in conjunction with radiation therapy or surgery ↑ survival)

Question 37

General prostate cancer treatment outline

Answer 37

Drug treatment radiation/ surgical removal of prostate

Question 38

Bicalutamide PK absorption | route of administration, bioavailability with food

Answer 38

PO tablets → absorbed well orally Bioavailability not affected by food ⇒ can take before/ after food Taken OD together with GnRH analogue

Question 39

Bicalutamide PK distribution

Answer 39

Highly plasma protein bound

Question 40

Bicalutamide PK metabolism | (S) & (R); t1/2 of (R)

Answer 40

Extensive in liver (S)-bicalutamide [inactive]: rapidly cleared by glucuronidation (R)-Bicalutamide [active]: slowly hydroxylation (CYP3A4) ⇒ glucuronidation * t1/2 = 6 days

Question 41

Bicalutamide PK excretion

Answer 41

Parent drug & metabolite via bile & urine

Question 42

Bicalutamide SE | HF, NVDC, L, F, S

Answer 42

* Hot flushes * Nausea/ vomiting, constipation/ diarrhoea * ↓ Sexual desire/ ability (decreased libido) * Fatigue * Mild swelling ankles/ legs/ feet

Question 43

Bicalutamide contraindications

Answer 43

Women & children Patients with known hypersensitivity reaction to bicalutamide OR to any excipients of this product