2016 - Childress - Individualized Chemotherapy Flashcards
Which chemo drugs cause direct injury to DNA?
Antimetabolites
Platinums
Alkylating agents
Anthracyclines
Antitumor antibiotics
Which chemo drugs cause indirect DNA damage? (interaction with a protein or etc)
Antimetabolites
Taxanes
Vinca alkaloids
Anthracyclines
Top I/II inhibitors
Hydroxyurea
What is Therapeutic Index (TI)?
Dose required to produce a given probability of toxicity/dose required to give a definted level of anti-tumor efficacy
Which enzyme is deficient in 23% of cats that makes them sensitive to 5-FU?
DPD (dihydropyrimidine dehydrogenase)
The enzyme needed to breakdown 5-FU
Deficiency in which enzyme in cats make them susceptible to azathioprine?
TPMT (thiopurine methyltransferase)
Deficiency in which enzyme in humans can make them sensitive to irinotecan?
UGT-1A1 (UDP-glucoronosyl transferase 1A1)
Which protein does ABCB1(MDR1) gene produce? Which mutation is common in dogs? and why is it important?
ABCB1-1delta mutation
ABCB1 encodes P-glycoprotein, a membrane associated drug efflux pump which limits intracellular/interstitial accumulation of substrate drugs
Which sites P-glycoprotein are expressed more in?
Blood-tissue barriers: BBB, testis, placenta
Luminal excretory structures: intestine, biliary epithelium, renal tubular epithelium
Some tumors
Which chemo drugs are P-glycoprotein substrates?
Anthracyclines - DOX, daunorubicin, epirubicin (Streptomyces peucetius)
Vinca alkaloids - VCR, VBL, vinorelbin (Vinca rosea)
Taxanes - paclitaxel, docetaxel (Taxus brevifolia)
Epipodophyllotoxins - etoposide, teniposide (Podophyllum pelatum)
Actinomycin-D (Streptomyces spp.)
Small molecule inhibitors - imatinib, sunitinib (Streptomyces staurosporeus)
Which breeds have high prevalence of ABCB1-1delta mutation?
Herding breeds:
Collie, English shepherd, McNab, Australian shepherd, Shetland sheepdog, Old English sheepdog, Border collie, White GSDs, Longhaired whippet, Silken windhound
What type of mutation is ABCB1-1delta mutation?
4 base pair deletion -> frame shift mutation -> premature stop codon
If a purebred dog that does not have a herding breed lineage is very sensitive to chemo, could it be because of ABCB1-1delta mutation?
NO
Based on Gustafson et al’s PK model on ABCB1-1delta muted dogs:
Is plasmal PK different in wt/wt and mut/mut dogs?
What would be most probably the dose-limiting side effect in these dogs?
What is the equipotent dose in mut/mut dogs to avoid these side effects?
Which other organ was expsed more in mut/mut dogs?
No
GI side effects, 3X DOX exposure to GI in mut/mut vs wt/wt
Reduce DOX dose to 10.7 mg/m2 in mut/mut doags
Liver, 65% greater exposure in liver
How should we dose dogs with ABCB1-1delta mutations?
No clinically validated standard
Avoid substrate drugs in mutants
Emperical dose reduction:
20-25% wt/mut; 50% in mut/mut, CAUTIOUS (5-10%) dose escalation if tolerated
Prophylactic supprotive care
Which physiologic variables scale directly with BSA?
Basal metabolic rate
Blood volume
GFR
Which physiologic variables DO NOT scale linearly with BSA?
Active renal secretion
Biliary secretion
Plasma albumin concentration
Hepatic biotransformation reactions
BSA-based dosing of which chemo drugs may increase toxic side effets in small dogs?
DOX, cisplatin, carboplatin, melphalan
What is the MTD of DOX in horses?
75 mg/m2
Should we change our dosing in obese animals?
NO.
PK study of 1200 human cancer patients suggested dosing based on actual body weight.
What is the carbo dose based on GFR in cats and people?
Bailey formula (cats)
Dose = Target AUC x 2.6 (GFR) x BW (kg)
Calvert formula (people)
Dose = Target AUC x (1.2 (GFR) + 25)
