5 - Overcoming PK-PD issues with cancer Flashcards
What are some benefits of combination therapy
Synergistic effect by inhibiting multiple important cellular pathways
Decreased risk of resistance
Risks of combination therapy
Increased toxicity profile
Increased risk of cross-resistance or multidrug resistance
What are pharmacokinetic issues of chemotherapy administration (2)
Mainly intravenous
Some oral - bioavailability, first pass metabolism, detoxification
What are pharmacokinetic issues of chemotherapy distribution (2)
Poor tumour vascularity (low conc of drug in tumour)
BBB for CNS tumours
What are some pharmacokinetic issues of chemotherapy metabolism and transport (4)
Comorbidity (decreased liver function Concurrent medication (induction/inhibition of ADR) Interpatient variability in menzymes Pro-drug metabolism needed to activate (irinotecan - SN38)
What are some pharmacokinetic issues with chemotherapy elimination (3)
Renal excreted drugs need good GFR
Many are toxic to kidney (cisplatin and methotrexate)
Overcome by increasing pH and urine flow
How was chemotherapy drug dose traditionally calculated
Normalisation methods
BSA
What are some issues with using BSA
Contributes very little variability in clearance
Inter-individual variability even with BSA normalisation
What are some difficulties for dose normalisation
Children (small but variable height and weight)
Extremes of ‘normal’ size range
(Dwarf vs giant)
(Obese vs low body weight)
What dose are obese patients capped at
2m2
What occurs with obese patients and chemo
Significant under-dosing and reduced efficacy
What was shown when obese patients were dosed according to ‘actual’ body weight
No increase in toxicity
Improved outcomes
What are doses routinely adjusted for (6)
Age Gender Other medication Performance status Liver function Renal function
What are some alternative dose normalisation strategies
For drugs with renal clearance - proportional to GFR
How are platinum drugs dosed
Calvert formula
What may be helpful to identify covariates to predict for sub-groups with reduced outcomes
Post-marketing studies or clinical trials
Why are pharmacoepidemiology studies difficult to perform
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)
