THERAPEUTIC DRUG MONITORING

NIKEN PUSPA
MUHAMMAD FADHIL

Vycke Yunivita, dr., M. Kes

 INTRODUCTION
• Therapeutic drug monitoring (TDM) is generally defined as the
clinical laboratory measurement of a chemical parameter
that, with appropriate medical interpretation, will directly
influence drug prescribing procedures.
• It involves the use of drug concentration measurements in
body fluids as an aid to the management of drug therapy for
the cure, alleviation or prevention of disease.
• TDM enables the assessment of the efficacy and safety of a
particular medication in a variety of clinical settings.
• The goal of this process is to individualize therapeutic
regimens for optimal patient benefit.
 CONCEPT OF THERAPEUTIC DRUG
MONITORING (TDM)
• TDM is based on the principle that for some drugs there is a
close relationship between the plasma level of the drug and its
clinical effect.
• If such a relationship does not exit TDM is of little value.
• The clinical value of plasma level monitoring depends on how
precisely the treatment outcome can be defined.
• When a precise therapeutic end point is difficult to define,
monitoring of drug levels may be of considerable therapeutic
assistance.
 THERAPEUTIC RANGE/ THERAPEUTIC
WINDOW
• The therapeutic range/ therapeutic window is the
concentration range of drug in plasma where the drug has
been shown to be efficacious without causing toxic effects in
most people.

Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1–10
 TDM -INDICATIONS

Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1–10
BASIC PRINCIPLES OF THERAPEUTIC
DRUG MONITORING
• The following are important considerations to ensure an optimum
TDM service in any setting:
1. Measurement of patient’s serum or plasma drug concentration
taken at appropriate time after drug administration
2. Knowledge of pharmacological and pharmacokinetic profiles of
the administered drugs
3. Knowledge of relevant patient’s profile like demographic
data, clinical status, laboratory and other clinical
investigations
4. Interpretation of SDC after taking into consideration all of the
above information and individualizing drug regimen according
to the clinical needs of the patient.
 PROCESS OF TDM
• Development of plasma profile in each patient
1) Administering a predetermined dose of drug
2) Collection of blood samples
3) Determination of blood samples
4) Plasma profile and pharmacokinetic model development:
– Clinical effect of drug
– Development of dosage regimen
– Diagnosis, dosage form selection, dosage regimen, initiation of
therapy

EVALUATION OF CLINICAL RESPONSE

 SAMPLES
•Sample selection must include an appropriate matrix.
 Plasma or serum is commonly used for drug assays.
Whole blood:- for Cyclosporine, tacrolimus, sirolimus, as there are
large shifts of drug between red cells and plasma with storage and
temperature change.
Saliva, which gives a measure of the unbound drug concentration,
may be a useful alternative when blood samples are difficult to collect.
Ex: Phenytoin ,Lithium, Amitryptyline

•Before collecting the sample:

 Establish that SDC is at steady-state

 Ensure complete absorption and distribution
• Samples should be collected and centrifuged as soon as
possible.
• Avoid serum-separator tubes because these may lower drug
concentrations due to the adsorption of drug into the matrix.
• Storage of samples: Plastic cryovial type tubes are acceptable
for most assays.
• For CSA: Whole blood to be collected in an EDTA tube.
• Analytical methods may be affected by temperature and all
variables should be standardized.
 GUIDELINES TO SPECIMEN COLLECTION
• Drawn blood, used for TDM, demonstrates a drug action in the
body at any specific time. Therefore, blood testing is the procedure
of choice when definite data are required.
• For adequate absorption and therapeutic levels to be accurate, it is
important to allow for sufficient time to pass between the
administration of the medication and the collection of the blood
sample.
• Blood specimens for drug monitoring can be taken at two different
times: during the drug´s highest therapeutic concentration (‘peak’
level), or its lowest (‘trough’ level).
• Occasionally called residual levels, trough levels show sufficient
therapeutic levels; whereas peak levels show toxicity.
• Peak and trough levels should fall within the therapeutic range.
• Patients receiving a drug at a dosing interval longer than the half-life
of the drug will demonstrate large fluctuations between peak and
trough levels.
• Plasma concentrations of drugs dosed at intervals shorter than their
half-lives would show less fluctuation between peak and trough
levels.
• For chronically administered oral medications the peak levels
usually occur 1-2 hours after the dose and the trough serum
concentration shortly after the dose is administered.
• Digoxin is one exception. The serum level to determine peak activity
should be drawn after the serum digoxin has had time to equilibrate
with the tissue i.e., 6-10 hours after the oral dose.
• Drawing the trough level at the time the dose is given is usually
sufficiently accurate.
• Intravenous medications should also be given time to equilibrate
before the peak level is drawn. They should be sampled ½-1 hour
after administration.
• For example, the peak serum level of Gentamicin should be drawn
thirty minutes after infusion of the drug ends and not immediately
after the infusion.
• Intramuscularly administered medications if injected in an area with
good blood flow will achieve peak levels within a similar time frame
as intravenous.
• Medications that are poorly soluble at body pH, however, may
precipitate at the site of injection and achieve very low and late
peak serum levels.
• The clinician should know what questions are to be answered
by the sample being drawn as different questions may require
different sampling times and possibly different numbers of
samples.
• For example the question of toxicity may be answered by only
one stat sample whereas a determination of half-life will
require at least two samples drawn at a more precise time
after the drug is administered.
• For patients suspected of symptoms of drug toxicity, the best
time to draw the blood specimen is when the symptoms are
occurring; i.e., immediately at the time of presentation.
 TIMING OF SAMPLE COLLECTION

• The best sampling time is in the predose or trough phase, when a

drug is administered by multiple oral doses.
 Trough conc. are commonly used for many drugs.
 Peak conc. may be useful for some antibiotics: Aminoglycosides
 Correct sample timing should also take into account absorption and
distribution, eg digoxin samples are collected after 6 hours of
administration.
 TIMING OF SAMPLE COLLECTION
 For short half-life drugs, more than one sample (three is ideal) is
the most useful for determining individual pharmacokinetic
parameters. Alternatively, a peak (CMAX) and a trough (CMIN) can
be collected to determine the bounds of high and low
concentrations at steady-state.
 For long half-life drugs (digoxin, phenobarbital), a single sample
during the dosing interval is sufficient. If one suspects altered
clearance rates, more samples can be collected to assess half-life.
 For cyclosporine, a single trough sample has been used for many
years, but now recommendations are changing to a single two
hour sample (C2). For cyclosporine a “trough” usually refers to a
12 hour sample, even though this drug is used once a day, or
once every other day in some patients.
 SAMPLE TIMING FOR SOME IMPORTANT DRUGS

a) Phenytoin: Since phenytoin has a long half life a single daily dose may be
employed and so the timing of concentration monitoring is not critical.
b) Carbamazepine: Its half life may be as long as 48 h following a single dose. A
trough concentration taken just after a dose together with a peak level 3 hours
later is ideal.
c) Digoxin: The measurement must be made atleast 6 hours after a dose to avoid
inappropriate high levels.
d) Theophylline: This drug has a narrow therapeutic index and timing of sampling is
not critical if the patient is receiving one of the slow release formulations, wherein
trough levels should be taken.
e) Lithium: A 12 hr sample gives the most precise guide to dosage adjustment.
f) Gentamicin: Pre dose peak; 0.5 hr after i.v. And 1 hr after i.m. administration.
 FACTORS THAT AFFECT RESULTS
• Pharmacokinetics
• Pharmacodynamics
• Dose
• Sampling time and type
• Testing methodology
• Genetic polymorphisms
• Other variables: Smoking, drug formulation and circadian
effect, use of Alternative system of medicine.
{shankhapushpi vs phenytoin}
• Interaction with conventional drugs have been documented
for liquorice, ginseng, tannic acids, plantain, uzara root,
hawthorn and kyushin.
 Pharmacokinetic and Pharmacodynamic
Variability

Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol. 2008;52(S1):5–9.
Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1–10
 INTERPRETIVE CRITERIA
• Therapeutic ranges: These are the recommendations derived by
observing the clinical responses of a small group of patients
taking the drug.
• The lower limit is set to provide ~50% of the maximum
therapeutic effect, while the upper limit is defined by toxicity.
• Therapeutic ranges are not absolutes and hence expert clinical
interpretation of the obtained value is necessary to derive
meaning from the result.
• Data on duration of drug therapy, dosage and time of the last
dosage is important.
• True TDM testing takes into consideration all the factors that can
affect results and interpretation.
 FACTORS THAT AFFECT INTERPRETATION
• These vary from drug to drug.
Protein Binding
• TDM assays typically require serum or plasma and usually measure both the
bound and unbound drug, even though it is the unbound drug that reacts
with the receptor to produce a response.
• This is seldom an issue – unless the patient’s binding capacity is altered
due to disease-state, drug interaction, or non-linear binding. In such cases,
the effect of the protein binding needs to be taken into consideration when
interpreting results.

Active Metabolites
• Many therapeutic drug metabolites, though not measured, contribute to a
drug’s therapeutic response. For example, primidone treatment is
monitored by measuring phenobarbitone, an active metabolite, but
primidone itself and other metabolites are also active.
Steady State
• Unless a loading dose or i.v. infusion is used initially, steady state
must be reached before meaningful TDM is possible for those drugs
that are given long-term.
Turnaround Time
• Turnaround time is important to ensure that the physician has time to
evaluate the result before the patient is scheduled to receive the
next dose.
• For most drugs this is not an issue, as assays for the most commonly
tested analytes are available on several fully automated analyzers.
• However, for drugs without commercially available assays, highly
specialized chromatographic and ultra-filtration assays are used.
These methods require specially trained staff and are most often
performed in a limited number of sites. Therefore, results tend to
take longer to receive.
 TECHNIQUES FOR MEASUREMENT OF TDM
• HPLC: High Pressure Liquid Chromatography: The separation of a substance
depends on the relative distribution of mixture constituents between two phases, a
mobile phase (carrying the mixture) and a stationary phase.

• LC/MS: Liquid Chromatography Mass Spectrometry: All chromatography-based

techniques work on the principle that different substances are absorbed differently
in solution. Two “phases” or materials are used to separate the components of a
solution. The mobile phase carries the sample along the stationary or solid phase,
which separates out the components in the sample.

• GC/MS: Gas chromatography is a separation method using very high temperatures

to cause sample vaporization. In mass spectrophotometry the vaporized fractions
are passed through an electrical field. The molecules can be separated on the basis
of molecular weight. The pattern of separation is unique to each drug and therefore
establishes a “fingerprint” for identification. GC/MS is the gold standard method
for the identification of drugs of abuse.
• EIA: Enzyme immunoassay. EIA uses a non-radioactive enzyme label. Most of the
drug testing today is performed using homogeneous EIA techniques. This refers to
the fact that the assays are performed in a single step, i.e. only one antibody is
used in the procedure. Therefore, the turnaround time for testing is reduced.

• RIA: Use radioactivity to detect the presence of the analyte. In RIA, the sample is
incubated with an antibody and a radio-labeled drug. The amount of radioactivity
measured is compared to the radioactivity present in known standards which are
included in each run. Results are quantitative.

• PETINIA: An immunoturbidimetric method; Particle Enhanced Turbidimetric

Inhibition Immunoassay. This method uses the creation of light scattering particles
to measure drug levels.

• EMIT: Enzyme Multiplied Immunoassay Technique; based on competition for the

target analyte antibody binding sites.
• FPIA: Fluorescence Polarization Immunoassay. This method uses a fluorescent
molecule as the label instead of an enzyme, making it more sensitive.
• Chemiluminescence: This is a chemical reaction that emits energy in the form of
light. When used in combination with immunoassay technology, the light produced
by the reaction indicates the amount of analyte in a sample. The most common
chemiluminescent assay methods are either enzyme-amplified or direct
chemiluminescent measurements.
• ACMIA: Affinity Chrome-Mediated Immunoassay. ACMIA is a technique to
measure drug concentrations in which free and drug-bound antibody enzyme
conjugates are separated using magnetic (chrome) particles.
• CEDIA: Cloned Enzyme Donor Immunoassay. CEDIA employs a recombinant DNA
technology.
 CLINICAL SIGNIFICANCE OF TDM
1. Maximizes efficacy
2. Avoids toxicity
3. Identifies therapeutic failure
– Non compliance, subtherapeutic dose
4. Facilitates adjustment of dosage
New dose = Old dose X Desired Css/Old Css
5.Facilitates the therapeutic effect of drug by achieving target
drug concentration
6. Identify poisoning, drug toxicity and drug abuse
 REFERENCES
• Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J
Intern Med. 2009;24(1):1–10.
• Gross AS. Best practice in therapeutic drug monitoring. Br J Clin
Pharmacol. 2008;52(S1):5–9.
• Hazarika I. Therapeutic Drug Monitoring (TDM): An Aspect of Clinical
Pharmacology and Pharmacy Practice. Res Rev A J Pharmacol.
2015;(January 2015):27-34.