therapeutic drug monitoring (TDM) Flashcards
what is therapeutic drug monitoring (TDM)?
the clinical practice of measuring drug concentrations (‘levels’) to optimize medication therapy for an individual patient
the process of TDM is predicted on what assumption?
that there is a definable relationship between dose and concentration, and between concentration and therapeutic/toxic effect
drugs that are good candidates for TDM
-drugs with a narrow therapeutic range/index (concentration associated with therapeutic effect overlap considerably with the concentration associated with toxic effects, such that the zone for therapeutic benefit without toxicity is very narrow)
TDM is employed for…
- medications having a narrow therapeutic range/index
- medications with a concentration-dependent efficacy/safety profile
- medications with marked PK and/or PD variability
medications routinely monitored through TDM
- anti-seizure medications
- cardiac medications
- antibiotics
- immunosuppressants
what is therapeutic (reference) range?
- range of drug concentrations within which the probability of:
- the desired clinical response is relatively high and
- the probability of toxicity is relatively low
specific range for a given drug varies based on…
- indication (type/site of infection and/or infecting organism/MIC with antibiotic treatment)
- treatment stage (e.g. time post-transplant with immunosuppressant treatment)
- dosing method (e.g. traditional vs extended-interval vs continuous infusion dosing strategies)
- concurrent treatment (e.g. drugs with additive toxicity)
amino glycoside treatment
- peak and trough with traditional dosing
- and random level(s) with extended-interval dosing
vancomycin treatment
trough only
phenobarbital
- post-loading dose level
- ~2-3 hours post-dose to confirm a therapeutic concentration plus follow-up levels (trough typical, but sampling time is not important because the long half-life minimizes peak-to-trough level fluctuation)
when should levels be ordered for a medication indicating TDM?
- treatment initiation
- dose adjustment
- change in concomitant medications having drug-drug interaction
- change in clinical status (e.g. renal/liver impairment)
- inadequate response (to confirm therapeutic level)
- signs/symptoms toxicity (to rule out toxic level)
- routine monitoring (e.g. in the outpatient setting)
how frequently should levels be ordered for a medication indicating TDM once therapeutic levels are achieved = aminoglycoside treatment
- every 3-7 days
- sooner in hemodynamically unstable patients, if clinical status changes, or if signs/symptoms toxicity observed
for vancomycin treatment
- every ~7 days, if indicated
- sooner in hemodynamically unstable patients, if clinical status changes, or if signs/symptoms toxicity observed
for phenobarbital
- following establishment of the maintenance dose per post-loading dose level
- a follow-up level may be collected 3-4 days later (before attainment of steady-state)
- and then 3-4 weeks later (after attainment of steady-state)
effect of renal dysfunction on renally cleared drugs?
-renal dysfunction will extend the t1/2 of renally cleared drugs
to appropriately interpret a drug level, you will need to collect/assess the…
- medication name and formulation (i.e. immediate-release vs extended-delayed-release)
- number of medication doses (at the current dose) that were administered prior to collection of the level (i.e. steady-state achieved?)
- medication administration time (i.e. timing of the dose prior to the collected level -> # hours post-dose?)
- sampling time (i.e. the time at which the level was collected - is it true peak/trough level, or was it collected early/late? was the level collected during the ‘distribution phase’?)
- historical levels (if available), and
- compliance/adherence (if indicated)
steady-state
- at steady-state, the rate of drug entering the body = the rate of elimination
- we typically want to know the drug concentration at steady-state
- with respect to TDM, a drug that has attained steady-state is at its highest concentration, and when given at the same dose at a fixed interval, the concentration vs time profiles are constant from dose to dose
peak
- steady-state maximum concentration
- typically measured 1/2 to 1 hour post-infusion
trough
- steady-state minimum concentration
- typically measured just prior to dose
- true tough occurs at the end of the interval (e.g. true trough is 8 hours post-dose with a q8h dosing schedule)
if the concentration is deemed to be subtherapeutic…
-increase the dose or shorten the dosing interval
if the concentration is deemed to be supratherapeutic/toxic…
-decrease the dose or extend the dosing interval
TDM steps for the pharmacist…
- choose the target concentration specific for a given patient and his/her medical condition
- initiate treatment regimen to attain the pre-defined target concentration using population PK parameters while accounting for an individual patient’s clinical condition and baseline characteristics including but not limited to age, weight, organ function [e.g. renal dysfunction], concomitant drug therapy, and/or historical levels
- analyze the collected drug concentrations
- evaluate response in light of the resulting drug concentrations
- adjust the regimen as indicated using PK parameters specific to a given patient based on the drug concentrations and/or response
steps to individualize drug therapy
- perform drug-drug interaction check for all concomitant medications
- many other steps
drugs that require TDM
- narrow therapeutic index
- variable pharmacokinetics: inter and intra patient variability
- known concentration-effect relationship (efficacy and/or toxicity)
therapeutic window vs therapeutic index
not the same
indications for TDM
- pharmacokinetic dose individualization
- monitor compliance
- monitor for drug interactions
- ensure efficacy/prevent toxicity
common drugs that require TDM: vancomycin
- trough = 10-20 mcg/ml
- AUC = 400-600 mg h/l
- anti-bacterial
common drugs that require TDM: gentamicin/tobramycin
- peak = 6-8 mcg/ml
- trough = 1-2 mcg/ml
- anti-bacterial
common drugs that require TDM: phenytoin
- random = 10-20 mcg/ml
- anti-seizure
common drugs that require TDM: warfarin
- INR (international normalized ratio) = 2-3
- anti-coagulant
pharmacokinetics
- what the body does to the drug; how the drug moves throughout the body
- ADME
absorption
-disintegration, dissolution, passive/active diffusion through enterocytes of GI tract (bioavailability; first pass metabolism)
distribution
binding of drug to proteins and tissues, distribution of drug throughout body
metabolism
enzymatic alteration of drug molecule primarily in liver, increases ability of molecule to be eliminated
elimination
removal of drug from systemic circulation primarily in kidney
pharmacodynamics
- what the drug does to the body
- receptor binding = affinity of drug for receptor
clearance (CL)
- volume of plasma that is cleared of drug per unit time
- specific to each drug; units typically L/hr
- may approximate creatinine CL if drug undergoes majority renal CL
apparent volume of distribution (Vd)
- pharmacokinetic rate constant - NOT A PHYSIOLOGIC TERM
- specific to each drug; units typically L
- may be represented as a fraction of weight
elimination rate constant (ke)
ke = CL/Vd
AUC
- area under the curve
- overall drug exposure
t1/2 (half-life)
-time at which drug has lost half its maximum concentration
steady state
- 4-5 half lives to achieve steady state
- amount of drug into system = amount of drug out of system
- peak and trough concentrations are consistent for each dose
steady state: ideal vs reality
- ideally, TDM should be performed at steady state for all drugs
- in reality, there are many indications for TDM before achieving steady state -> ensure effective concentrations achieved to combat life-threatening infections, prevent accumulation in patients with severely reduced CL (renal or hepatic failure)
affect of kidney dysfunction on pharmacokinetics
- increase volume of distribution
- decrease kidney elimination
affect of kidney dysfunction on pharmacodynamics
- increased permeability of the blood brain barrier -> increased CNS effects
- decreased platelet aggregation -> increased bleeding risk
assessment of kidney function
- Cockcroft-Gault estimation of CrCl
- calculate CrCl and Ideal Body Weight (IBW) in kg
- creatinine is a product of muscle (protein) catabolism, therefore select the body weight that most closely resembles muscle mass
creatinine clearance (CrCl)
[140 - age (years) x ideal body weight (kg) / [72 x SCr (mg/dl)]
-multiple by 0.85 if female
ideal body weight (IBW) in kg for females
IBW = 45.5 + (2.3 x height > 5’ in inches)
ideal body weight (IBW) in kg for males
IBW = 50 + (2.3 x height > 5’ in inches)
affect of hepatic dysfunction on pharmacokinetics
-decrease hepatic metabolism
affect of hepatic dysfunction on pharmacodynamics
- altered effect of certain drugs due to altered sensitivity
- increase permeability in the BBB, increases in GABA (inhibitory neurotransmitter)
- less albumin production in the liver -> decrease protein binding -> increase free drug available to act
liver function assessments: Child-Pugh Score
Class A, Class B, Class C
-least to most severe
class A
5-6 points
class B
7-9 points
class C
10-15 points
vancomycin clinical pharmacokinetics
-initial dose = 15-20 mg/kg
ke formula
ke = CL/Vd
t1/2 formula
t1/2 = ln2/ke = 0.693/ke
phenytoin TDM
interpretation of phenytoin concentration data is obscured in renal dysfunction due to alterations in protein binding, volume of distribution, and free drug available
renal dysfunction patient taking phenytoin
- draw FREE drug concentration whenever possible
- it has an effect on volume distribution
warfarin principles
- vitamin K antagonist
- anti-coagulant
- narrow therapeutic index
- numerous drug and food interactions
warfarin = INR too low
blood clots more likely
warfarin = target INR
- usually 2-3
- balance of benefits and risks
warfarin = INR too high
bleeding side effects more likely
warfarin clinical pharmacokinetics
- onset of effect is 2-3 days
- duration of effect is 2-5 days
- half life of factor II (thrombin) is 72 hours
- age, weight, renal function, hepatic function, genetics, concomitant medications, diet all affect dosing
