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Therapeutic Drug Monitoring

Roger L. Bertholf, Ph.D.


Chief of Clinical Chemistry & Toxicology
Shands Jacksonville Medical Center

Why monitor plasma drug


concentrations?

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

Ke
Elimination

K-d

Tissue

Drug absorption
Route

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 Distribution

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

Vd (L/Kg)

Amikacin
Gentamycin/Tobramycin
Phenytoin
Primidone
Theophylline
Valproic Acid
Ethanol

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

ke
Elimination

k-d

Tissue

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?

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

Time

TDM methods

HPLC
RIA
FPIA
EMIT
CEDIA

Chromatography
Separation of components based on their. . .
Solubility in mobile and stationary phases

Terminology:

Gas/liquid
Liquid/liquid
Ion exchange
Partition

Chromatographic separations

Mobile Phase
Stationary Phase

Chromatographic separations

Soluble in stationary phase


Long retention time

Soluble in mobile phase


Short retention time

Detector signal

Chromatographic separations

A
B

The resolution of a chromatographic


separation is defined as:
t/mean peak width

Time

What is the effect on resolution?

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

Radioimmunoassay
Fluorescence Polarization Immunoassay
Enzyme-Multiplied Immunoassay Technique
Cloned Enzyme Donor Immunoassay

Theophylline

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)

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

Most frequently prescribed anticonvulsant


Vd = 1.0 L/Kg
Therapeutic range: 10 - 20 g/mL
Toxicity at > 20 g/mL

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