5 - Overcoming PK-PD issues with cancer

Question 1

What are some benefits of combination therapy

Answer 1

Synergistic effect by inhibiting multiple important cellular pathways
Decreased risk of resistance

Question 2

Risks of combination therapy

Answer 2

Increased toxicity profile

Increased risk of cross-resistance or multidrug resistance

Question 3

What are pharmacokinetic issues of chemotherapy administration (2)

Answer 3

Mainly intravenous

Some oral - bioavailability, first pass metabolism, detoxification

Question 4

What are pharmacokinetic issues of chemotherapy distribution (2)

Answer 4

Poor tumour vascularity (low conc of drug in tumour)

BBB for CNS tumours

Question 5

What are some pharmacokinetic issues of chemotherapy metabolism and transport (4)

Answer 5

Comorbidity (decreased liver function
Concurrent medication (induction/inhibition of ADR)
Interpatient variability in menzymes
Pro-drug metabolism needed to activate (irinotecan - SN38)

Question 6

What are some pharmacokinetic issues with chemotherapy elimination (3)

Answer 6

Renal excreted drugs need good GFR
Many are toxic to kidney (cisplatin and methotrexate)
Overcome by increasing pH and urine flow

Question 7

How was chemotherapy drug dose traditionally calculated

Answer 7

Normalisation methods

BSA

Question 8

What are some issues with using BSA

Answer 8

Contributes very little variability in clearance

Inter-individual variability even with BSA normalisation

Question 9

What are some difficulties for dose normalisation

Answer 9

Children (small but variable height and weight)
Extremes of ‘normal’ size range
(Dwarf vs giant)
(Obese vs low body weight)

Question 10

What dose are obese patients capped at

Answer 10

2m2

Question 11

What occurs with obese patients and chemo

Answer 11

Significant under-dosing and reduced efficacy

Question 12

What was shown when obese patients were dosed according to ‘actual’ body weight

Answer 12

No increase in toxicity

Improved outcomes

Question 13

What are doses routinely adjusted for (6)

Answer 13

Age
Gender
Other medication
Performance status
Liver function
Renal function

Question 14

What are some alternative dose normalisation strategies

Answer 14

For drugs with renal clearance - proportional to GFR

Question 15

How are platinum drugs dosed

Answer 15

Calvert formula

Question 16

What may be helpful to identify covariates to predict for sub-groups with reduced outcomes

Answer 16

Post-marketing studies or clinical trials

Question 17

Why are pharmacoepidemiology studies difficult to perform

Answer 17

PBS - large volume of data but no dose information or individual clinical information attached
Medical records - pharmacy records not always linked and not easily available
Electronic records - some available - supplies can limit
Data linkage - Different databases and different jurisdictions (multiple ethics applications)