TDM Flashcards
What is therapeutic drug monitoring?
The measurement of blood drug concentrations for the purpose of ensuring adequate and effective treatment while avoiding potential toxicity.
What is the therapeutic and toxic response to a drug directly related to?
The therapeutic (and toxic) response to a drug is directly related to its concentration at some specific “receptor”
AND
The blood concentration of the drug reflects the concentration at the target receptor.
We can’t sample the receptor.
What is the concept of the therapeutic range?
A range of serum drug concentrations associated with effective therapy but w/o significant toxicity or side effects
Analogous to reference interval
Derived from clinical studies (drug trials)
Why do TDM?
Optimize dose and therapeutic response
—Undertreatment may be dangerous
Avoid toxicity
—-Overtreatment may be dangerous
Detect changes or variability in pharmacokinetics
Monitor compliance
—Is the patient taking the drug as prescribed?
What is pharmacokinetics?
What the body does to a drug
ADME stands for?
Absorption
Distribution
Metabolism
Elimination
What is pharmacodynamics?
What the drug does to the body
effects and mechanism of action
A single drug dose does ____result in the same ________dose in everyone.
NOT,
DOSE CONCENTRATION
Pharmacological response is caused by ?
free drug bound to receptor site
What are three ways to administer drugs? Describe the absorption and variability for each.
Intravenous administration
- –“instantaneous” and complete – not a variable
- –requires professional administration = cost
Intramuscular or subcutaneous
—-slower
Oral
What is meant by distribution of a drug? What can it be affected by?
Delivery of a drug to various compartments
central – blood (and interstitial fluid) = ECF
peripheral – other tissues/organs
Distribution is affected by:
- —binding to blood proteins
- —lipophilicity (high distribution by depositing in fat)
- —specific binding in tissues (ie: digoxin bound up in heart and muscle/specific receptors bind tightly
Why do we not draw drug levels during distribution phase?
Because blood levels overestimate how much drug is actually taken up by tissues.
Drug levels should be drawn AFTER distribution is complete.
What are two proteins that bind drugs?
Albumin
- –binds acid & neutral drugs
- ——–phenytoin, carbamazepine, VPA
α1-acid glycoprotein (AAG, orosomucoid)
—binds basic drugs
——lidocaine, tricyclic antidepressants
acute phase reactant (increases during acute reaction)
—Drugs bound ≥90% may be appropriate for free drug measurement (don’t do often)
How are drugs eliminated?
Hepatic Metabolism
—hepatic disease may alter dosing for drugs —–cleared primarily by metabolism
Renal Elimination
—decreased creatinine clearance (eGFR) may alter dosing for drugs cleared by excretion
During drug metabolism how does the body’s reaction affect metabolism?
Reactions are designed to “de-toxify” the drug and/or increase its polarity for urinary excretion
Reactions may also form active drug (prodrug) or a toxin
Hepatic cytochrome P450 (CYP) system
18 CYP families, 43 sub-families, involved in:
drugs & other (3 families: CYP1, CYP2, CYP3)
genetic variability – pharmacogenetics (-omics)
warfarin –
VKORC1 – warfarin target
CYP2C9 – warfarin metabolism
Michaelis-Menton kinetiics relationship to drug metabolism?
Michaelis-Menten kinetics (1st order to drug)
- –metabolizing enzymes are in excess of drug concentration
- –doubling dose approximately doubles drug concentration
- –True for most drugs at typical therapeutic concentrations
Saturation kinetics (zero order to drug) ---therapeutic concentrations overload metabolic enzymes ----inc. dose has a disproportionate increase in drug level -----phenytoin (therapeutic range ~ sat’n) ethanol (sat’n at >0.02%) – legally drunk = 0.08%
In first order kinetics (exponential) elimination rate depends on ? (most drugs eliminated by first order kin)
drug concentration
What is a drug half-life?
Half-life (T½): the time for the blood drug concentration to decrease by 50%
What is the peak?
Peak – time at which the concentration (at the site of action) is highest
- –draw after distribution phase complete
- –not commonly used (Antibiotics only?)
What is trough? JBND?
Trough – time of the lowest concentration
JBND – just before next dose
appropriate draw time for most drugs
What is steady state in repetitive dosing?
DEFINITE TEST QUESTION
Steady-state – net equilibrium between drug intake and elimination
Time to reach steady-state is solely a function of half-life
Don’t draw levels before 4-5 half-lives from initiation or after change in dosing
When do we use TDM?
- Drugs with narrow (low) therapeutic index
- Treatment failure – distinguish compliance vs. unusual pharmacokinetics
- Assess adequacy when clinical indicators evasive
- –prevent seizures, don’t titrate
- —prevent rejection, don’t hope to salvage
- Toxicity mimics disease (digoxin, PA, phenytoin)
- Toxicity cannot be tolerated
- Likely PK aberrations (drug interactions, polymorphisms, hepatic or renal disease, pregnancy)
What is the therapeutic index?
Therapeutic Index = Toxic conc. ÷ Therapeutic conc.
TDM measuring methods
Immunoassay – preferred method for most
- homogeneous (EMIT, CEDIA, KIMS)
- –adaptable to most standard chemistry analyzers
- fluorescence polarization – Roche Integra
- heterogeneous – often chemiluminescent
- –standard immunassay analyzers
HPLC – flexible but poorly automated
—Useful if no commercial assay available
(manual work ie precipitation before)
-mult drugs can be measures unlike immunoassay
GLC – ditto, but often requires derivatization, sometimes drugs dont exist in gas form
When should TDM be sampled?
- Steady-state required (4-5 half-lives)
- JBND (just before next dose, “trough”) – suitable for most drugs.
- Peak – occasionally for antibiotics
- —well-defined for i.v. drugs
- –more variable for oral, i.m. or subcutaneous
- –relation to distribution phase
- Ideally, dosing info is available – but reality?
- —dose, time of dose, route (CAP checklist)
What are TDMs drawn in?
Gel barrier tubes:
SST (B-D) – dec. in phenytoin, lidocaine, carbamazepine
Corvac (Tyco Kendall) – dec. in lidocaine only
Greiner – no effects? (no peer-reviewed study?)
Gel adsorbs or dissolves drug. Decrease is dependent upon drug, sample volume and duration of contact
Reference labs usually have blanket no SST rule for all drugs, whether affected or not
What is the only Cardioactive drug that is monitored today really?
Digoxin
Uncommonly monitored:
Procainamide
Lidocaine
Quinidine
Rarely monitored
flecainide, tocainide, amiodarone, verapamil, disopyramide, diltiazem, nifedipine
Digoxin
Natural product – foxglove plant
Therapeutic 0.8-2.0 ng/mL, toxicity may be seen at 1.5 ng/mL
= LOW THERAPEUTIC INDEX
children may tolerate up to 4.0 ng/mL
Renal excretion req. dosage adjustment in renal disease
Half-life 30-45 hrs
Long distribution: draw ≥8 hrs post dose (JBND preferred)
Increased toxicity with ↓K+, ↓Mg2+, ↑Ca2+
Quinidine → ↑digoxin levels
Measure by immunoassay
Digoxin assay interferences?
DLIS – digoxin-like immunoreactive substance
steroids – synthesized in the adrenal (“cardenolides”)
increased in pregnant women and newborns
increased in renal, hepatic and cardiac failure
assay dependent interference – check drug-free patients
Aldactone (spironolactone) - K+ sparing diuretic
neg. interference – IMx, AxSym, Dimension
pos. interference – TDx, Elecsys
no interference – EMIT, Vitros, Tina-Quant (Roche latex)
Fab fragment of digoxin antibody
Given to treat digoxin overdose
May interfere (positive) with digoxin assays:
marked – Immulite, Vitros, Dimension, Access
moderate – Elecsys, Integra, EMIT, Centaur
minimal – AxSym, Synchron, CEDIA
Ultrafiltration allows “accurate” free digoxin level
Procainamide
Hepatic metabolism – N-acetylation to NAPA
PA and NAPA both active, always measure both
Fast acetylators (half-life ~3 hrs)
PA:NAPA ≥ 1.0 @ 3 hr post dose
Slow acetylators (half-life ~5 hours)
PA:NAPA > 2.0 @ 3 hrs post dose
more likely to develop lupus-like syndrome
Japan - 10%, Mediterranean - 90%, U.S. Caucasian - 50%
Measure by immunoassay, HPLC
Anticonvulsants
Carbamazepine (CBZ, Tegretol®), Oxcarbazepine (Trileptal®) Phenobarbital (ΦB); Primidone (Mysoline®) Phenytoin (DPH, Dilantin®), Fosphenytoin (Cerebryx®) Valproic Acid (VPA, Depakene®) Primidone (Mysoline®) Ethosuximide (Zarontin®) Clonazepam (Klonopin®) Gabapentin (Neurontin®) Lamotrigine (Lamictal®) Felbamate (Felbatol®) Zonisamide (Zonergan®) Levitiracetam (Keppra ®) Tiagabine – (Gabitril®)
Carbamazepine (CBZ)
Tegretol® 80% protein bound (± free drug monitoring) Hepatic metabolism – induced by DPH, ΦB, and CBZ CBZ-10,11-epoxide active metabolite may accumulate in children w/ nl CBZ Erratic absorption T1/2 15-20 hrs Therapeutic range 4-12 mcg/mL Monitor trough levels
Phenytoin
Dilantin® - diphenylhydantoin (DPH)
~90% protein bound
candidate for free drug monitoring (esp. in renal patients)-things displacing pheny from albumin increasing free and decreasing bound
Low H2O solubility: erratic oral & im absorp.
Hepatic metabolism – T1/2 ≈ 20 hrs
metabolism begins to saturate >5 mcg/mL
induced by EtOH, PB and CBZ
comp. by cimetidine, dicumarol, INH
Protein binding competition by ASA and VPA
Collect samples JBND (no SST tubes)
Therapeutic range 10-20 mcg/mL, critical >35-40
Free phenytoin – therapeutic range 1.0-2.0 mcg/mL
90% bound, 10% free
Phebobarbital
40-60% protein bound
Hepatic metabolism – T1/2 70-100 hrs
draw trough levels
Induces metabolism of other drugs (DPH, CBZ)
Dec. clearance with VPA and ASA (↑10-20%)
Ther. range 15-40 mcg/mL, critical >80 mcg/mL
Primidone
Mysoline®
Metabolized to phenobarbital (PB) (T1/2 = 10 h)
monitor both, steady state depends on phenobarbital
Therapeutic range 5-12 mcg/mL, toxic >15 mcg/mL
DPH → ↑ PB:Prm due to dec. PB metab.
VPA decreases clearance of PB and Prm
Collect JBND
Valproic Acid
Depakene®
Hepatic metabolism (T1/2 16→12 hrs, 8 in children)
short T1/2 in children can lead to subtherapeutic levels
>90% protein bound, dec. in uremia, cirrhosis
competes w/ DPH (slide 15)
Hepatotoxic – monitor LFT’s (esp. ALT)
Not recommended during pregnancy (teratogenic)
Draw JBND
Theophylline
Aminophylline, TheoDur (sustained release)
bronchodilator – asthma, neonatal apnea
largely replaced by ß2-agonists
Hepatic metabolism (half-life 3-11 hrs)
saturation occurs ≈ 20 mcg/mL
Therapeutic range 10-20 mcg/mL, toxic >25-30
Neonatal apnea – 5-10 mcg/mL (caffeine preferred)
Peak – 2 hrs w/o food, 3-5 w/ food or SR
Measure peak or trough (rare now)
Caffeine
Treat neonatal apnea Advantages over theophylline: less frequent dosing more central respiratory stimulation less peripheral cardiovascular toxicity Therapeutic range – 8-20 mcg/mL Measure by HPLC or immunoassay
Which antibiotics can we use TDM on?
Aminoglycosides Gentamicin, Tobramycin, Amikacin Vancomycin Anti-tubercular INH, Rifampin, Ethambutol, Pyrazinamide Rare
Aminoglycosides
Gentamicin, Tobramycin, Amikacin
Bactericidal against aerobic gram-negatives
O2 dependent active transport into bacteria
often combined w/ cell wall Abx (e.g., penicillins)
Poor oral absorption, given iv or im
Vd ≈ 0.2 L/kg, consistent with blood & ECF
Vd – volume of distribution
100% renal excretion, T1/2 2-3 hrs
Renal disease req. dec. dose and/or inc. dosing interval
***nephrotoxic
Historical protocol for Aminoglycosides
Historical protocols:
dosed tid (3/day, iv or im), draw peak & trough
peak – 4-10 mcg/mL (20-30 amikacin)
15-30 min. post iv infusion
2 hrs post im-injection
trough - therapeutic (?)
nephrotoxicity (reversible) at trough > therapeutic
Modern protocol for Aminoglycosides
Current protocols: Once-a-day dosing same total dose (3-5 mg/kg IBW/day) no levels if 60 mL/min goal is 18 hr post level
Aminoglycosides sampling
Heparin – binds aminoglycosides, blocks antigenicity (hep neg and amino positive so attracts and then antibodies cant see aminogly so false low levels)
No green top tubes
Carbenicillin, ticarcillin, piperacillin
covalent binding – blocks antigenicity and action
assay quickly or freeze after separation
Measured by immunoassay
Vancomycin
Glycopeptide – unrelated to aminoglycosides
Effective against gram-pos bacteria
Enterococci developing resistance (VRE)
Given iv
Monitor by immunoassay:
peak (30 min post iv) – 30-50 mcg/mL
trough (JBND) – 5-15 (to 20 in hosp. acquired pneumonia, osteomyelitis)
ototoxicity and nephrotoxicity low (historical?)
CDP-1 – degradation product that cross-reacts in some assays, esp. in renal patients
Poor standardization among manufacturers
Up to 35% variance
Immunosuppressants
Cyclosporine A
Tacrolimus (ProGraf, FK-506)
Sirolimus (Rapamycin)
Mycophenolic acid
All are isolated from molds
Block T-lymphocyte proliferation via several mechanisms
Prevent T-cell mediated organ rejection
Cyclosporin A
Targets levels vary with organ and duration of therapy
Whole blood is preferred sample
Draw trough levels after 3-5 days therapy
Measure by immunoassay (req. pretreatment) or LC-MS/MS
Many metabolites, therefore immunoassay results may be higher than LC-MS/MS, esp. with polyclonal assays
Tacrolimus
Less nephrotoxic than cyclosporine Slight neurotoxicity in ≤5% of patients Therapeutic range 3-15 ng/mL Collect whole blood after at least 5 days Measure by immunoassay or LC-MS/MS
Sirolimus
Structural, mechanistic similarity to FK-506
Collect whole blood JBND after 3 days
Measure by LC-MS/MS or immunoassay
Keep trough levels >30 ng/mL for 8 wks, then maintain >15 ng/mL
Values above 60 ng/mL associated with significant complications
Mycophenolic Acid (MPA)
MMF - prodrug hydrolyzed in liver to MPA Conjugation to MPA-glucuronide (MPAG) Monitor trough levels in serum/plasma: MPA – 1.0-3.5 mcg/mL MPAG – 35-100 mcg/mL (value?) Immunoassay or LC-MS/MS
Psychoactive drugs
Lithium
(Tri)cyclic antidepressants
SSRI’s – selective serotonin reuptake inhibitors
Antipsychotic (neuroleptics)
*Except for lithium, rarely need monitoring
Lithium
Used to treat manic phase of bipolar disorder
Administered as Li2CO3. Draw JBND
Very low therapeutic index
therapeutic range: 0.5 -1.2 mM
mild toxicity: >1.5 mM (not life-threatening)
severe toxicity: >2.5 mM (seizures)
Renal excretion, dehydration increases toxicity
Therapeutic effects are delayed
Lithium Measurment
Flame photometry – outdated Atomic absorption (flame) - cumbersome Ion-selective electrode – semi-automated Electrode has slight Na interference Measure (and QC) both Na & Li and correct mathematically Chemical – adaptable to chemistry analyzers Substituted proprietary porphyrin Li-dependent phosphatase
