Anticancer PK/PD Flashcards
How are cancer cells generated?
Multiple gene mutations
Solid tumors
Carcinomas and sarcomas
Hematological tumors
Lymphomas, leukemias
Treatment types
Surgery, radiation therapy, chemo, targeted therapy, immunotherapy, blood product donation and transfusion, stem cell transplant, vaccine, hyperthermia, photodynamic therapy, lasers
Neoadjuvant therapy
Given before the surgical procedure to shrink cancer and procedure doesn’t have to be as extensive
Adjuvant therapy
Destroy leftover cancer cells that may be present after the tumor is removed to prevent reoccurrence
First-line
Treatment best to treat a certain cancer
Second-line
Use if first-line doesn’t work, aka salvage therapy
Palliative
Supportive care
Cell cycle phase-specific agents
Appear to be most active during a particular phase but can be active in another phase
Cell cycle phase-nonspecific agents
May have greater activity in one phase than another but not to the degree of cell cycle phase-specific agents
PK of anticancer agents
Most have a narrow TI and wide inter-individual PK –> TDM
Consequence of not being able to predict anticancer PK
Increased toxicity or sub-therapeutic dosing
Effects/causes of decreased absorption of anticancer agents
N/V, prior surgery, radiotherapy, chemo affecting GI tract, DDI, decreased peristalsis
Effects/causes of increased absorption of anticancer agents
DDI, increased peristalsis
Effects/causes of decreased distribution of anticancer agents
Weight loss, decreased body fat
Effects/causes of increased distribution of anticancer agents
Hypoalbuminemia, protein binding, peritoneal or pleural effusions
Effects/causes of decreased elimination of anticancer agents
Decreased renal and/or hepatic dysfunction
Effects/causes of increased elimination of anticancer agents
Induction of metabolism
Indicator of efficacy
Toxicity
Efficacy of MTX is associated with what?
Cmax
PD drug interaction between 5-FU and leucovorin
Leucovorin enhances the effect of 5-FU by inhibiting thymidylate synthase
PD DDI between cisplatin/carboplatin and paclitaxel/docetaxel
Administration of paclitaxel followed by carboplatin lead to a decrease in the formation of platinum adducts in patient DNA (aka decreasing the toxicity of carboplatin)
Dose individualization: BSA-based
BSA has minimal clinical value in achieving consistent drug exposure but using BSA to dose adjust is still widely used
A priori dose adjustment: renal function
Carboplatin is the only drug that’s dosed based on GFR
A priori dose adjustment: propensity for toxicity
Based on history of chemo and physiological status of patients, their propensity to manifest the known toxicity can be predicted and adjusted
A priori dose adjustment: elderly and obesity
Aging can’t be considered as an independent feature (can’t be used to adjust doses alone)
Limitation of calculated BSA at 2.2m^2 recommended for obese patients
A priori dose adjustment: pharmacogenetics
5-FU is catabolized by DPD and patients who don’t have much of this enzyme are at risk of life-threatening toxicity
6-MP is inactivated by TPMT and there’s polymorphic populations that have different dose adjustments
Dose adjustment based on population PK
Run a trial and get the PK, put it into some software and it builds a population model
Limitation of LSM
Need to be applied and validated in treatments using the same anticancer agents, doses, administration schedules, and duration of infusion as the original study the LSM was established
Rescue therapy for MTX toxicity
Leucovorin
PK matrixes used to establish a correlation with efficacy/toxicity
AUC, Css, Cmax, time above a threshold concentration
