Pharmaceutics 1 Cancers

Question 1

Name 5 different anti-cancer drugs and give examples

Answer 1

Cytotoxics (doxirubicin and vinblastine)
Steroids (dexamethasone)
Biological agents (trastuzumab)
Hormone therapies (tamozifen)
Bisphosphonates

Question 2

Why are cancer drugs the target for new drug formulation?

Answer 2

Many drugs are toxic to healthy cells as well as cancerous.

Existing cytotoxic drugs have narrow therapeutic window and are dosed at or close to the maximum tolerated dose (MTD)

Question 3

What is a key problem that must be overcome in biological drugs?

Answer 3

They would be degraded if taken orally

Question 4

Which three things will be improved with better formulation?

Answer 4

Safety, bio-distribution and thus efficacy

Question 5

What are some of the problems with drug delivery so far? Refer to diagram in handout.

Answer 5

Drug remains in circulation and doesn't diffuse out to target tissue
Kidney excretion 
Liver excretion (bile)

Question 6

With reference to an example, what are the general problems with formulation / specificity at a cellular level i.e. receptor.

Answer 6

Pazopinib is a tyrosine kinase inhibitor and is indicated for kidney cancer and soft tissue sarcoma.
The drug molecule has to enter the right cell and also kinase domain i.e. VEGFR-1. Ligand binding domain to cross cell cytosol and transmembrane domain to the intracellular kinase domain. Other competing molecules for the ligand binding site is PIGF, VEGF-B and VEGF-A.

Question 7

What problem is faced in the delivery of Doxirubicin?

Answer 7

Needs DNA interaction, so nuclei penetration of cells.

Question 8

What factors influence choice formulation for anti-cancer drugs?

Answer 8

The physiochemical and biopharmaceutical properties of the drug candidate.
The intended dose and route of administration (potency of drug and duration of action).
Disease factors such as the type of cancer and location.

Question 9

What biological factor can cause variation between patients and give two examples?

Answer 9

Native enzymes i.e. converting drugs from pro drugs to their active form
CYP3A4
ABCB1

Question 10

Why is the dose of chemotherapy often at the MTD?

Answer 10

Maximum tolerated dose used to reduce the risk of drug resistance

Question 11

Pros and Cons to Oral ROA

Answer 11

Subject to first pass metabolism
Drug has to be absorbed via the gut
Stays in the stomach for 30-45 mins
90% of the oral medication is metabolised by the liver before reaching the bloodstream
Fed/fasted variability (Nilitonib (TKI) shows a large increase in F with a high fat meal
Drug rapidly transported around the body once it has reached systemic circulation
Blood from intestines is taken to the liver for detoxification

Question 12

What forms of parenteral administration are there?

Answer 12

IV
IM
SC
Minor routes (IT, IA, IArticular, ICardiac

Question 13

What are the pros to parenteral administration?

Answer 13

Avoids nausea and vomiting problems on administration
Accurate dosing (100% F)
Flexible dose and regimen 
Rapid onset of action
Rapid withdrawal of the drug
No fed/fasted effect
Avoids first pass metabolism

Question 14

What are the requirements for IV formulation?

Answer 14

Sterile production
Formulation stability (particle size, solubility, clearance time, targeting)
No preservatives and low excipients (ideal as reduces the potential incompatibilities such as physical adsorption or chemical complexation).

Question 15

What are the pros and cons to subcutaneous ROA

Answer 15

Muscles are highly vascularised so rapid absorption seen in drugs with high solubility.
Implants, suspensions, colloids
High collagen in muscle means that charged drugs can bind

Question 16

What are the challenges with topical formulation and what are some examples?

Answer 16

Drug needs to be retained at the skin
Tretinoin for malignant melanoma
Tretinoin cream is 0.05% w/w in w/o emulsion