Pharmaceutics of Anticancer drugs

Question 1

What is the process of a drug going through the body?

Answer 1

Drug injected into vein -> goes to heart -> pulmonary circulation -> pumped around tissues -> blood flow into tissues is slow; efficient absorption -> drug returns to heart through liver- metabolism begins. This ‘trip’ takes 10-30 seconds

Question 2

Where is doxorubicin distributed to?

Answer 2

lungs, liver, spleen and kidneys

Question 3

What is the active metabolite of doxorubicin?

Answer 3

Doxorubicinol

Rapid metabolism

Question 4

What are the problems with doxorubicin?

Answer 4

• Rapidly cleared from blood post injection, triphasic blood clearance
• 50% excreted in bile within 7 days
• Does not cross BBB but may placenta
• Cardiotoxocity is dose-limiting
• Not predictable pharmacokinetics
• Binds to proteins

Question 5

What are doxorubicin triphasic profiles?

Answer 5

12 mins, 3.3 hours and 30 hours.

Question 6

Complications with doxorubicin injection

Answer 6

Doxorubicin is a severe irritant and can cause thrombophlebitis, extravasation (leakage) after injection can cause local necrosis and ulceration.

Question 7

How do you avoid systemic toxicity?

Answer 7

• Enhanced Permeation and Retention (EPR) effect

* Encapsulate doxorubicin into virus-sized carrier

Question 8

In tumours, what happens to the endothelial wall?

Answer 8

the endothelial wall is disrupted; some particulates and large molecules can go across the barrier and are retained. This is due to the change in the integrity of the blood vessels surrounding the tumor, and inflammation changes the transport materials.

Question 9

why would encapsulating doxorubicin be beneficial?

Answer 9

If you encapsulate doxorubicin and use a carrier you avoid the exposure to healthy cells as it circulates, and some of the drug will go into the tumour, small molecules will be pumped back out by efflux pumps

Question 10

What factors effect the EPR effect? (enhanced permeation and retention)

Answer 10

• Vehicle related: plasma residence time, particle size, carrier vehicle and polymer architecture.
• Tumour-related: Tumour type and microenvironment ( different density)
• External Mediators: Radiation, Bradykinin antagonist, Cyclooxygenase inhibitor, nitric oxide scavengers

Question 11

What are the passive targeting factors?

Answer 11

• Prolonged blood circulation; drug carriers delivered to target tissues
• Obstacles to long circulation:
- Glomerular excretion; avoided by using carriers, taking into account the SIZE (> 42-50kDa)
- RES recognition; foreign bodies are coated and marked for destruction (needs to be avoided)

Question 12

What is a good size, charge and shape for even distribution to tissues?

Answer 12

• 20-150nm
• Negative or neutral

(see sheet)

Question 13

What is included in liposomal doxorubicin?

Answer 13

1) Poly(ethylene) corona
2) Phospholipid bilayer
3) Doxorubicin hydrochloride

Question 14

What is the role of the PEG in Liposomal doxorubicin?

Answer 14

Polymer chains from the surface, strongly hydrated; for a protein to bind they have to displace a water, therefore proteins ‘bounce off’.
- Prevents attachment of plasma proteins, entropic stabilization, and preventing aggregation during transit to tumors.

Question 15

Role of hydrochloride in liposomal doxorubicin?

Answer 15

• Loaded by pH gradient
  Less soluble in neutral form, pH changes to slightly alkaline so it precipitates and increases drug loading and self-association of drug in liposome

Question 16

Disadvantage and advantage for liposomal doxorubicin?

Answer 16

• Longer circulation time allows passive transport to tumour tissue with disrupted vasculature; accumulation in tumour.
  • Liposomes are highly diluted on injection; potential drug leakage during transport and need to balance stability of liposome and drug release.

Question 17

Why might reduced pH have benefit in solid tumours?

Answer 17

as retained liposomes have a longer time in lower pH. Protonated = more solid, deprotonated= dissolve in tumors

Question 18

Complication with not all tumours having the EPR effect?

Answer 18

• The EPR effect is not present for all tumors, also there could be unwanted accumulation at sites with poor circulation -> palmar-plantar syndrome: damage to finger, toes and peripheral sites.

Question 19

Advantages to liposomal delivery

Answer 19

 Small molecules diffuse in and out of tumors easily
 Small molecules can be pumped out via efflux pumps
 Liposomes also diffuse into leaky tumors
 Uptake of liposomes into cancer cells bypasses transporter proteins in cell membranes
 Release of doxorubicin intracellularly avoids efflux pumps
 No efflux pumps for liposomes.

Question 20

Problems with PACLITAXEL

Answer 20

• Potent drug that is insoluble in water

- Formulation with polyoxyl castor oil and alcohol, can cause hypersensitivity

Question 21

What is the solution to the Paclitaxel problems?

Answer 21

• Formulate paclitaxel within a nanoparticle pre-formed from albumin and PTX.
• Exploits the albumin receptor gp60 mediated transcytosis across endothelial cells
• Helps to concentrate drug in tumours due to binding of albumin to SPARC (secreted protein, acidic and rich in cysteine) receptor
- Proteins aggregate and precipitate s the formulation becomes stable, pre to injection.

Question 22

What is the mode of action of paclitaxel?

Answer 22

1) Administration followed by rapid dissolution and
dissociates into particles in blood.
2) Binds to SPARC receptors are over expressed
on some tumours.
3) Activation of transcytosis, internalization of Albumin,
and release of drug into tumour interstitium
4) Tumour uptake and cell death

Question 23

Is tamoxifen a weak base or weak acid?

Answer 23

Weak Base

Question 24

Does tamoxifen have good solubility?

Answer 24

Low aqueous solubility

Question 25

Mode of action of tamoxifen

Answer 25

• Pro-drug- antagonist of estrogen receptor in breast cancer via active metabolite 4-hydroxytamoxifen; in other tissues (endometrium), it is an agonist; self-formulating drug.

Question 26

What enzymes drive tamoxifen’s pharmacokinetics?

Answer 26

• PK driven by metabolism by CYP3A4, CYP2C9 and CYP2D6; variation between patients.

Question 27

Why are the tamoxifen metabolites key in antineoplastic effect?

Answer 27

They bind to estrogen receptor but do not activate it.
4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) have 30-100 times greater affinity with the estrogen receptor than tamoxifen.