IPC Kidney: Drug Therapy Individualization (Week 3)

why do we individualize drug therapy?

improve pt outcomes, reduce cost of drug treatments, expand pharmacists scope of practice, prevent legal ramifications

what are some risks associated with individualizing drug therapy?

risk of efficacy failure, toxicity, litigation, career

what are characteristics of drugs that require TDM?

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

what is ED50?

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

what is TD50?

dose where 50% of the patients get unwanted side effect

what is the difference between therapeutic window and therapeutic index?

window: range of effective drug dose between minimal effective concentration and minimum toxic concentration

index: number that quantifies the width of that range

what are the 4 indications for TDM?

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

what is the definition of TDM?

the use of assay procedures for determination of drug concentrations in plasma, and the interpretation and application of the resulting concentration data to develop safe and effective drug regimens

what are common drugs that require TDM?

vancomycin, gentamicin/tobramycin, phenytoin, digoxin, lithium, valproic acid, warfarin, heparin

what is the therapeutic range for vancomycin?

trough 10-20 mcg/ml, **AUC 400-600 mgh/L

what is the therapeutic range for gentamicin/tobramycin (aminoglycosides)?

peak 6-8 mcg/mL (for efficacy), trough 1-2 mcg/mL (for toxicity)

what is the therapeutic range for phenytoin?

random 10-20 mcg/ml (neither trough or peak, about 4-6 hours after admin)

what is the therapeutic range for warfarin?

INR 2-3

what are the 4 PK parameters?

CL, Vd, elimination rate constant Ke, half life

elimination rate constant Ke =

CL/Vd

half life =

0.693/ke

what is Cmax?

highest concentration of drug in the blood

what is Cmin?

lowest concentration of drug in the blood

what is half life?

time at which drug has lost half of its max concentration

what is AUC?

overall drug exposure

after 1 half life what % of drug is remaining?

50

after 2 half lives what % of drug is remaining?

25

after 3 half lives what % of drug is remaining?

12

after 4 half lives what % of drug is remaining?

6

after 5 half lives what % of drug is remaining?

3

after 6 half lives what % of drug is remaining?

1

after 7 half lives what % of drug is remaining?

0

___ half lives to reach steady state

4-5

during SS, peak and trough concentrations are...

consistent for each dose

ideally, TDM should be performed at ___ for all drugs

SS

in reality, there are many indications for TDM before achieving SS including...

ensuring effective concentrations achieved to combat life-threatening infections, preventing accumulation in pts with severely reduced CL (renal or hepatic failure)

what is the affect of kidney dysfunction on ADME? (PK)

absorption can increase/decrease/stay the same, **Vd increases, hepatic metabolism decreases/stays the same, ***kidney elimination decreases

what are the 2 affects of kidney dysfunction on PD?

increased permeability of BBB increases CNS effects, decreased platelet aggregation increases bleeding risk

what is the equation for cockcroft-gault CrCl?

((140-age)IBW)/(72SCr) * 0.85 if female

what is the IBW formula for males?

50 + (2.3 * (height-60))

what is the IBW formula for females?

45.5 + (2.3 * (height-60)

what is the affect of hepatic dysfunction on ADME? (PK)

absorption increases/stays the same, Vd increases/stays the same, ***hepatic metabolism decreases, kidney elimination decreases/stays the same

what are the affects of hepatic dysfunction on PD?

altered effect of certain drugs due to altered sensitivity, increased permeability in BBB increases GABA, less albumin production in the liver decreases protein binding and increases free drug available to act

which drug class' PD is affected by hepatic dysfunction?

benzodiazepines, 30% greater psychomotor impairment in cirrhotic pts despite similar drug concentrations as healthy controls

hepatic dysfunction causes an increase in GABA, what does this do?

inhibitory neurotransmitter that can increase sedation

a child pugh score of 5-6 is...

class A mild hepatic dysfunction

a child pugh score of 7-9 is...

class B moderate hepatic dysfunction

a child pugh score of 10-15 is...

class C severe hepatic dysfunction

what are examples of primary resources for drug information?

medical literature, drug studies

what is the best source of information for truly individualized info?

primary resource

which type of resource can search for drug studies with pts very similar to those seen in specific clinical practice setting?

primary

what are examples of secondary resources for drug information?

meta-analyses, systematic reviews, package inserts

what are general examples of tertiary resources for drug information?

textbooks, drug information books, online resources

what are some specific examples of tertiary resources for drug information?

lexicomp, clinical pharm, AHFS hospital formulary, physician's desk reference, dipiro's pharmacotherapy

which type of resource is not always up to date but a good place to start?

tertiary

what are the principles of vancomycin?

bactericidal antibacterial agent, growing resistance concerns, optimize AUC/MIC, gram positive coverage including MRSA

what is the coverage for vancomycin?

gram positive including MRSA

what is the initial dose for vancomycin?

15-20 mg/kg

what is the maintenance dose for vancomycin?

10-15 mg/kg every 8-12 hours if normal renal function

efficacy of vancomycin correlates with...

AUC/MIC >400

toxicity of vancomycin is correlated with...

trough >15 mg/L or AUC >600

what are the principles of phenytoin?

Na+ channel blocker anti-epileptic, non-linear PK michaleis menten, very narrow therapeutic index, numerous drug interactions

what is the therapeutic range for total and free concentration of phenytoin?

total: 10-20 mg/L, free: 1-2 mg/L

what is the protein binding of phenytoin?

highly protein bound to albumin (90%)

what is the primary elimination of vancomycin?

unchanged in the urine, renal elimination

what is the protein binding of vancomycin normally and in ESRD?

moderate protein binding normally 30-55%, low protein binding in ESRD 10-25%

interpretation of phenytoin concentration data is obscured in renal dysfunction due to...

alterations in protein binding, Vd, and free drug available

if a pt has renal dysfunction, how do we measure phenytoin concentration?

draw free drug concentration whenever possible

concentrated phenytoin =

measured phenytoin concentration/ (adjustment factor ( albumin) + 0.1

you ONLY use corrected phenytoin in pts with...

hypoalbuminemia or kidney dysfunction

what is the phenytoin adjustment factor for CrCl >20 ml/min?

0

what is the phenytoin adjustment factor for CrCl <20 ml/min?

0

what are the principles of warfarin?

vitamin K antagonist anticoagulant, narrow therapeutic index, numerous drug and food interactions

what is the onset of effect for warfarin?

2-3 days

what is the duration of effect for warfarin?

2-5 days

what is the half life of factor II (warfarin)?

72 hours

what factors affect dosing of warfarin?

age, weight, renal function, hepatic function, genetics, concomitant medications, diet

what is the clearance of warfarin?

hepatic via CYP2C9

what is the protein binding of warfarin?

highly protein bound, 99% to albumin

what is the INR therapeutic range for most indications of warfarin?

2-3

what is the INR therapeutic range for pts with a mechanical valve on warfarin?

2.5-3.5