Therapeutic Drug Monitoring

what types of drugs require TDM

narrow therapeutic index + variable PK (inter- and intra-patient variability) + known concentration-effect relationship (efficacy and/or toxicity)

T/F: therapeutic window and therapeutic index are not the same thing

true

what does ED50 mean

the dose where 50% of the patients get the desired therapeutic effect

what does TD50 mean

the dose where 50% of the patients get unwanted side-effects

how does therapeutic window differ from therapeutic index?

concentration based and usually based on individual not populations

what are some indications for TDM?

PK dose individualization, monitor compliance, monitor for drug interactions, and ensure efficacy/prevent toxicity

TDM definition:

monitoring drug concentrations to ensure efficacy and minimize toxicity

common drugs that require therapeutic drug monitoring

vancomycin, gentamicin/tobramycin, phenytoin, and warfarin

therapeutic range for vancomycin:

trough 10-20 mcg/mL or AUC 400-600 mg*h/L

therapeutic range for gentamicin/toobramycin:

peak 6-8 mcg/mL and trough 1-2 mcg/mL

therapeutic range for phenytoin

random 10-20 mcg/mL

therapeutic range for warfarin:

INR 2-3

what is clearance

volume of plasma that is cleared of drug per unit time

what is apparent volume of distribution (Vd)?

PK rate constant - NOT A PHYSIOLOGIC TERM and may be represented as a fraction of weight

Ke =

Cl/Vd

half-life =

0.693/ke

define Cmax

highest concentration of drug in blood

define half-life

time at which drug has lost half its maximum concentration

define Cmin

lowest concentration of drug in blood

define AUC

overall drug exposure

how many half-lives to steady state?

4-5 half-lives

define steady state

amount of drug into the system = amount of drug out of system

what is true regarding the peak and trough concentrations at steady state?

consistent for each dose

T/F: time to steady state is independent of dosage

true

when is it ideal for TDM to be performed?

at steady state

initial dose of vancomycin

15-20 mg/kg

what value correlates with efficacy of vancomycin

AUC/MIC > 400

what value correlates with toxicity (nephro) correlates with vancomycin

trough > 15 mg/L or AUC > 600

what value correlates with efficacy of aminoglycosides

peak concentrations 5-10 mg/L for gentamicin/tobramycin and peak concentrations of 20-30 mg/L for amikacin

what value correlates with toxicity of aminoglycosides?

concentrations greater than target trough of < 2 mg/L for genta/tobra and < 10 mg/L for amikacin

what is a pearl of phenytoin TDM?

interpretation of concentration data is obscured in renal dysfunction due to alterations in protein binding, volume of distribution, and free drug available

target total phenytoin concentration?

10-20 mcg/mL

target free phenytoin concentrations

1-2 mcg/mL

what can occur if INR is too high

bleeding side effects more likely

what can occur if INR too low

blood clots more likely

onset of action for warfarin

2-3 days

duration of effect for warfarin

2-5 days

half life of factor II:

72 hours

target INR range for mechanical heart valves

2.5-3.5