Formulation Decisions for Cancer Drugs

Question 1

Why formulate cancer drugs?

Answer 1

• Many cancer drugs are toxic (to kill ANY cells they contact)
• Existing cytotoxics have a low therapeutic window
• Cancer drugs are dosed at or close to the maximum tolerated dose (MTD)
• Formulations are needed to improve safety, biodistribution and thus efficacy

Question 2

What do formulation choices for anticancer drugs depend upon?

Answer 2

• Physiochemical and biopharmaceutical properties of the drug candidate
• Intended dose and route of administration; potency and duration of action (potent drug requires lower dose, can inject; can’t inject large volumes due to low potency in same respect)
• Disease factors; type of cancer, location
• The patient
• ADME

Question 3

How does therapeutic window guide formulation?

Answer 3

• Narrow gap between effective and toxic dose for many cancer drugs (and most cytotoxics)
• Dosing schedules close to MTD (Max Tolerated Dose) to prevent build-up of resistance
• Variations in dosing/tolerance for patients can have SIGNIFICANT -ve impact on treatment outcome
• Cancer drug formulations often defined by route of administration which has simplest pharmaceutics profile
  »> Need to know how much of the dose hits the target!

Question 4

What factors are in play when an anticancer is taken orally?

Answer 4

• Subject to first pass metabolism
• Drug has to be absorbed by the small intestine, but first VIA gut
• Stays in the stomach for 30-45 mins
• 90% of orals metabolised by liver before reaching bloodstream
• Drug then rapidly transported around the body
• Portal circulation; blood from intestines is taken to liver for detoxification
• Fed/fasted effects; e.g. with Nilotinib (TKI, log P ~ 4.4), there is a large increase in bioavailability with a high fat meal
  »> Thus one patient could be easily overdosed, one underdosed.
• CYP could be upregulated in some patients (metabolised faster) than others = different dosing required

Question 5

What does parenteral mean, and what are examples of such formulations?

Answer 5

• Not via gut; injected formulations
• IV
• IM
• SC
• Minor routes: intrathecal, intraarterial, intraarticular, intracardiac, intracisternal, intrapleural

Question 6

What are the advantages of using parenteral formulations (IV)?

Answer 6

• Avoids problems w/PO; N&V are common S/Es for most cytotoxics, thus patient doesn’t vomit it back out

IV:

• Accurate dosing (100% bioavailability)
• Flexibility of dose & dosing schedule
• Rapid onset of action
• Rapid withdrawal of drug (can just stop) e.g. toxicity
• No fed/fasted effect
• IV best to achieve therapeutic window

Question 7

What are the requirements for IV formulations?

Answer 7

Formulation stability:

• Particle size (ideally none; don’t want to cause occlusion)
• Solubility
• Clearance time
• Targeting
• Sterile production
• No preservatives
• Low excipients
  (reduce potential incompatibilities e.g. physical absorption, chemical complexation leading to precipitation)

Question 8

What are the advantages of subcutaneous formulation?

Answer 8

• Local or systemic effect
• Muscles highly vascularised = quick onset, rapid absorption for drugs w/good solubility
• Formulation requirements less severe; formulation doesn’t circulate bloodstream, only drug
• Implants, suspensions, colloids
• High collagen content in muscle; can bind charged drugs (collagen is a charged protein)

Question 9

When is topical formulation used?

Answer 9

• When drugs are needed to retain drug in/at skin

E.g. Tretinoin for malignant melanoma

Question 10

What factors contribute to the ‘snakes and ladders’ journey to formulating an anti-cancer agent?

Answer 10

- Aqueous solubility
>>> Delivery system
- IV or oral?
- S/Es
>>> Delivery system
- Refine formulation