Download Therapeutic Drug Monitoring

Therapeutic Drug Monitoring
Roger L. Bertholf, Ph.D.
Chief of Clinical Chemistry & Toxicology
Shands Jacksonville Medical Center
Why monitor plasma drug
concentrations?
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Avert toxicity
Optimize dose/therapeutic response
Detect changes in pharmacokinetics
Monitor compliance
First Principle of TDM
• “Knowledge of serum concentrations is
most helpful when the drug in question
requires individualized dosing for optimal
efficacy and more routine measures of
therapeutic success are unavailable.”
From W. J. Taylor and A. L. Finn (eds.) Individualizing Drug Therapy, 1981
Therapeutic Index
Toxicity
Toxic
Therapeutic range
Sub-therapeutic
Plasma drug concentration
Therapeutic Index
• High therapeutic index
– NSAIDs
• Aspirin
• Tylenol
• Ibuprofen
– Sedative/hypnotics
• Benzodiazepines
– Most antibiotics
– Beta-blockers
• Low therapeutic index
– Lithium
– Neuroleptics
• Phenytoin
• Phenobarbital
– Some antibiotics
• Gent/Vanco/Amikacin
– Digoxin
– Immunosuppressives
Introduction to Pharmacokinetics
• What are pharmacokinetics?
– The study of the absorption, distribution, and
elimination of drugs
– Pharmacodynamics is the study of drug effects
• Most drugs exert their effect at tissue
receptors, but we measure drug concentration
in plasma.
Two Compartment Model
Absorption
Ka
Kd
Blood
Tissue
K-d
Ke
Elimination
Drug absorption
• Route
–
–
–
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–
Oral
Intravenous
Intramuscular/subcutaneous
Dermal
Inhaled/intranasal
• Slow/sustained release
Rate of drug absorption
IV  Inhaled > Intramuscular > Oral > Dermal
seconds
minutes
hours
First-pass metabolism
Prodrug  Active drug
or
Active drug  Inactive metabolite
or
Lipid soluble drug  Water soluble drug
Two Compartment Model
Absorption
ka
kd
Blood
Tissue
k-d
ke
Elimination
Distribution () phase
• Once drug is absorbed into the blood, it
begins to distribute to tissues
• The amount of drug that partitions into
tissues depends on . . .
– Lipophilicity
– Protein binding
• The partitioning of drug between blood and
tissues is expressed quantitatively as the
Volume of Distribution
Volume of Distribution (Vd)
• The Volume of Distribution (Vd) is the
amount of blood, per Kg body weight,
necessary to contain all of the body burden
of drug at equilibrium concentration.
Total Body Stores
Plasma Concentration 
Volume of Distributi on
Low Volume of Distribution
Blood
High blood
concentration
(g/mL)
kd
Tissue
k-d
Low tissue
concentration
kd << k-d
 Vd is low
If kd = 0, Vd = 0.07 L/Kg (lower limit)
Drugs with low Vd
Drug
Amikacin
Gentamycin/Tobramycin
Phenytoin
Primidone
Theophylline
Valproic Acid
Ethanol
Vd (L/Kg)
0.05 – 0.70
0.07-0.70
0.70
0.60
0.50
0.20
0.53
High Volume of Distribution
Blood
Low blood
concentration
(ng/mL)
kd
Tissue
k-d
High tissue
concentration
kd >> k-d
 Vd is high
For highly lipophilic drugs, Vd may be  100 L/Kg
Drugs with high Vd
Drug
Vd (L/Kg)
Digoxin
500 – 600
Carbamazepine
0.8 – 1.9
Lidocaine
130
Procainamide
2.4
Propranolol
Quinidine
200 – 300
3.0
Interpreting Vd
• Drugs with low Vd are contained mostly in
the plasma, because . . .
– They are highly water soluble (plasma water
content is higher than tissues), or
– They are highly protein bound (which prevents
them from freely diffusing into tissues
• Drugs with high Vd are mostly in tissues, and
plasma levels may not reflect body burden
Example of Vd calculation
A 70 Kg man takes a 5 mg dose of phenobarbital (Vd = 1.0 L/Kg).
What is the maximum plasma phenobarbital concentration you
can expect?
5.0 mg
0.07 mg

 70 g / L
1.0 L
L
70 Kg 
Kg
Example of Vd calculation
A 55 Kg woman has a plasma theophylline (Vd = 0.5 L/Kg)
concentration of 15 g/L.
How much theophylline does she have on board?
15 g 0.5 L

 55 Kg  412.5 g
L
Kg
What can affect Vd?
• Body fat index (men vs. women)
• Tissue perfusion (CHF or edema)
• Concentration of plasma proteins
Plasma drug concentration
Effect of Vd on peak plasma level
Vd = 0.1
Vd = 0.2
Vd = 0.4
Time 
Two Compartment Model
Absorption
ka
kd
Blood
Tissue
k-d
ke
Elimination
Elimination () phase
• Can be renal, biliary, secretory, respiratory
• Often depends on metabolism
• Is the most variable pharmacokinetic
parameter
What factors affect the rate of
drug elimination?
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Hepatic function
Renal function
Urine pH
Genetic factors
Other drugs
Plasma drug concentration
Pharmacokinetics
Peak plasma concentration
t1/2

Time 

Plasma drug concentration
The Steady State
Peak
Therapeutic range
dose
Trough
d
d
d
Time
d
d
d
TDM methods
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HPLC
RIA
FPIA
EMIT
CEDIA
Chromatography
• Separation of components based on their. . .
– Solubility in mobile and stationary phases
• Terminology:
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Gas/liquid
Liquid/liquid
Ion exchange
Partition
Chromatographic separations
Mobile Phase
Stationary Phase
Chromatographic separations
A
B
Soluble in stationary phase
Long retention time
Soluble in mobile phase
Short retention time
Detector signal
Chromatographic separations
A
The resolution of a chromatographic
separation is defined as:
B
t/mean peak width
Time 
What is the effect on resolution?
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Increasing column length?
Decreasing/increasing solvent polarity?
Increasing flow rate?
Increasing temperature?
Increasing stationary phase film thickness?
HPLC Detectors
Detector
Sensitivity
Specificity
Cost
UV/Vis
Moderate
Low
Low
Fluorescence
Moderate
Moderate
Moderate
Refractive index
Low
Low
Low
Electrochemical
High
Moderate
Moderate
Moderate
High
High
Mass spectrometer
More recent TDM methods
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Radioimmunoassay
Fluorescence Polarization Immunoassay
Enzyme-Multiplied Immunoassay Technique
Cloned Enzyme Donor Immunoassay
Theophylline
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Bronchodilator
Therapeutic range: 5 - 20 g/mL
Neonates metabolize theophylline to caffeine
Vd = 0.5 L/Kg
Toxic at > 20 g/mL
– Nausea, vomiting, diarrhea, stomach pain,
headache, insomnia, tachycardia
– Seizures, cardiac arrhythmia at > 35 g/mL
Gentamycin/Tobramycin
• Wide-spectrum aminoglycoside antibiotics
• Vd = 0.2 L/Kg
• Therapeutic
– 4 - 10 g/mL (peak); 0.5 - 1.5 g/mL (trough)
• Toxic: 12 - 15 g/mL
– Ototoxicity
– Nephrotoxicity
Digoxin
• Improves cardiac output in CHF patients
• Vd = 500 - 600 L/Kg
– Highly bound to tissues
– What does this say about small changes in
plasma digoxin concentration?
• Therapeutic range: 1.5 - 2.0 ng/mL
• Toxic levels (> 2.0 ng/mL) produce
arrhythmias, GI, CNS symptoms
Procainamide
• Antiarrhythmic
• Active metabolite is NAPA
– N-acetyltransferase
– Fast vs. slow acetylators
• Vd = 2.4 L/Kg
• Therapeutic: 4 - 10 g/mL
• Toxicity: Heart block, n/v, diaphoresis, malaise
at Procainamide + NAPA > 30 g/mL
Carbamazepine
• Anticonvulsant, and for Rx of TGN
– Active in tonic-clonic (grand mal) sz
• Vd = 1.5 L/Kg (lipophyllic but 25% proteinbound
• Therapeutic range: 4 - 12 g/mL
• Toxicity in one fourth of patients
– Diplopia, drowsiness, nystagmus, ataxia, n/v
– Also, derm, hematol, hepatic
Phenobarbital
• Anticonvulsant (metabolite of Primidone)
– Long-acting barbiturate (t1/2 = 2 - 4 days)
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Vd = 1.0 L/Kg
Therapeutic range: 15 - 40 g/mL
Toxic symptoms at > 60 g/mL
Drug interactions (induction of hepatic
microsomal enzymes)
Phenytoin
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Most frequently prescribed anticonvulsant
Vd = 1.0 L/Kg
Therapeutic range: 10 - 20 g/mL
Toxicity at > 20 g/mL
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Nystagmus
Blurred vision
Ataxia
Drowsiness/Coma
Valproic acid
• Broad spectrum anticonvulsant, but mostly
used for absence (petit mal) seizures
• Vd = 0.2 L/Kg
• Therapeutic range: 50 - 100 g/mL (trough)
• Hepatotoxic