This document discusses the basic principles of therapeutic drug monitoring (TDM). It provides 3 key points: 1. TDM is a team effort that involves measuring drug concentrations in serum/blood, interpreting the results based on pharmacokinetics and the patient's clinical condition, and adjusting the drug regimen accordingly. 2. For optimal TDM, blood samples should be taken at steady state and appropriate times in relation to the last dose, analytical techniques should be sensitive enough to measure drug levels, and clinical information is needed to interpret results. 3. Factors like disease states, age, pregnancy, and drug interactions can impact drug levels and must be considered when interpreting results, along with the patient's clinical response

1. Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, 1, 87-95 87
E-ISSN: 2309-4435/13 © 2013 Pharma Professional Services
Basic Principles of Therapeutic Drug Monitoring
Ahmed S. Ali1,*
, Mahran S. Abdel-Rahman2
, Ab Fatah Ab Rahman3
and
Osman H. Osman1
1
Faculty of Medicine King Abdul-Aziz University, Saudi Arabia
2
Faculty of Pharmacy, Taibah University Saudi Arabia
3
Clinical Pharmacy Program, School of Pharmaceutical Sciences, University Sains Malaysia
Abstract: Therapeutic drug monitoring (TDM) is a tool that can guide the clinician to provide effective and safe drug
therapy in the individual patient. It is a team work service; the clinical pharmacist plays an important role to guide the
team. TDM involves not only measuring drug concentrations, but also the clinical interpretation of the result. This
requires knowledge of the pharmacokinetics, sampling time, drug history; the patient's clinical condition and specific
laboratory results. The following review summarize the criteria to insure optimal TDM service.
Keyword: Drug monitoring, Pharmacokinetics, optimal dosing.
1. INTRODUCTION
Therapeutic drug monitoring (TDM) has contributed
substantially in assisting patient management and has
become an important tool in clinical medicine. The
provision of TDM service requires a team effort from
various clinical services. In a typical TDM service, the
clinician will determine the initial dose of a drug. A
clinical pharmacist assists by providing essential
information about the drug, revises the initial regimen if
necessary, and provides a plan for TDM. A nurse or a
phlebotomist collects the blood sample at an
appropriate time. The nurse usually documents
essential information and clinical response of the
patient. Finally, a clinical laboratory scientist or chemist
performs the drug assays (Figure 1). Once the assay
*Address correspondence to this author at the Faculty of Medicine King Abdul-
Aziz University, Saudi Arabia; Tel: 0966568970438;
E-mail: Profahmedali@gmail.com
result is available, the clinical pharmacist provides
interpretation of the result and makes appropriate
recommendations to the physicians. A new drug
regimen will include drug dose, dosage interval, route
of administration, after taking into consideration patient-
specific factors such as age, weight, and renal function.
Recommendation of an appropriate drug regimen
takes into account the patient’s individualized
pharmacokinetics and clinical condition or response.
The following are important considerations to ensure
an optimum TDM service in any setting [1-3]:
(1) Measurement of patient’s serum or blood drug
concentration (SDC) 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, and
(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.
TDM when used properly helps to improve efficacy
and minimize toxicity of selected drugs especially those
with narrow therapeutic ranges or with marked
pharmacokinetic variability [4]. Table 1 shows drug
characteristics that may require monitoring of their
SDC. Commonly monitored drugs are shown in Table
2.

2. 88 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 2 Ali et al.
Figure 1: Role of health professionals in a TDM service.
Table 1: Common Drug Characteristics for TDM [5]
Drug with an established relationship between its SDC and therapeutic response and/or toxicity
Drug with a narrow therapeutic index. Example: Lithium, phenytoin, and digoxin
Drug with large individual variability at steady state SDC in any given dose
Drug with poor relationship between its SDC and dosage
Drug with saturable metabolism. Example: phenytoin
Drug with poorly defined end point or difficult to clinically predict the response. Example: immunosuppressant drugs
Drug whose toxicity is difficult to distinguish from a patient's underlying disease. Example: Theophylline in patients with chronic obstructive
pulmonary disease
Drug whose efficacy is difficult to establish clinically. Example: Phenytoin
Table 2: Commonly Monitored Drugs [4]
Drug class Examples
Cardio active drugs Digoxin; (amiodarone,)
Antibiotics gentamycin, amikacin
tobramycin, vancomycin
Antiepileptic drugs Phenytoin, phenobarbitone, valproic acid, carbamazepine
(ethosuximide); clonazepam
Bronchodilators theophylline (caffeine)
Immunosuppressant Cyclosporine and FK 506
Cytotoxic drugs methotrexate
Analgesic Acetaminophen and aspirin
Antidepressants and antipsychotics lithium and tricyclic antidepressants

3. Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 2 89
2. OPTIMIZATION OF TDM SERVICE
With wide availability of TDM services in hospitals
nowadays, there is a tendency that the service is being
misused or overused. Like other clinical services,
appropriate measures need to be taken to optimize its
use thus, ensuring the best clinical outcomes. There
are a number of criteria that need to be considered to
make TDM a cost-effective service [5-7].
There are clear clinical indications for the
measurement of SDC (e.g. no response to treatment;
suspected non-compliance; suspected toxicity).
The specimen (i.e. blood, serum or plasma) is taken
at an appropriate time and with identifiable patient
information.
Appropriate analytical techniques are available to
determine the SDC of the drug and/or its metabolites.
Adequate clinical information is available to allow
the interpretation of SDC.
2.1. Clear Indication for the Drug Level
Determination
TDM data supports the clinician to make
appropriate clinical decision but it should not be used
as a routine laboratory test. A rational indication of
SDC determination includes assessment of patient
compliance. For example, when a patient fails to
respond to a usual therapeutic dose, measurement of
SDC can help to distinguish between a noncompliant
patient and a patient who is a true non-responder. With
antibiotic therapy, TDM helps to determine whether
therapy failure is due to inadequate SDC or due to
bacterial resistance. TDM also provides early indicators
regarding toxicity or non-reversible adverse effects
before clinical symptoms are being observed. For
example, progressively high trough gentamicin
concentrations may provide early warning of potential
renal damage. TDM can also be used to confirm a
suspected drug interaction. For example, co-
administration of an enzyme inducer or inhibitor is likely
to affect the SDC and pharmacokinetics of cyclosporine
A, thus affecting its efficacy. Patients who have
impaired clearance of a drug with a narrow therapeutic
index will benefit from SDC monitoring. For example,
patients with renal failure have decreased clearance of
digoxin and therefore are at a higher risk of toxicity.
Providing TDM of digoxin in such patients will help
clinicians to adjust dose regimens accordingly [8-11].
2.2. Optimal Sampling Time
Sampling After Achievement of Steady-State
Condition
In most cases blood samples should not be
collected until a steady-state condition has been
reached. This occurs when the rate of drug
administration and drug elimination are equal, for most
drugs this is achieved after 4 to 5 half-lives. If a loading
dose has been administered, the desired drug
concentration may be achieved earlier. However, drug
concentrations may be determined earlier if toxicity is
suspected. It is important to wait for steady-state both
at initiation and following any dosage change [1]. In
certain situations A loading dose(an initial higher dose)
may be given at the beginning of a course of treatment
to rapidly achieve of steady state A loading dose is
most useful for drugs that are eliminated from the body
relatively slowly, i.e. have a long systemic half-life.
Drugs which may be started with an initial loading dose
include digoxin, and Phenytoin for acute status
epilepticus [12].
Sampling at the Appropriate Time in Relation to
Last Dose
When a drug is administered, it goes through the
stages of absorption, distribution, metabolism and
elimination. An essential requirement for some drugs is
to take the sample at the appropriate specified time
following the last dose [12, 13]. Errors in the timing of
sampling will produce abnormal or unexpected results.
Nurses and clinical pharmacists should always be
aware of correct sampling times to avoid
misinterpretation of results.
Accurate sampling time is critical for some drugs as
shown in the following examples:
Drugs with short half lives e.g. aminoglycosides (Figure
2);
Good correlation with AUC and hence efficacy e.g.
Cyclosporine A (2 hours post dose);
Avoid sampling during the distributive phase e.g.
Digoxin (at least 6 hours post dose);
Specific sampling time based on a nomogram e.g.
Acetaminophen toxicity (at least 4 hours post dose);
Specific sampling time e.g. Methotrexate (at various
time intervals according to institutional guidelines).

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2.3. Laboratory Considerations
Analytical Techniques
The analytical method should be sensitive, precise,
accurate, and specific enough to measure SDC within
the reference range. It should allow rapid analysis to
ensure the provision of TDM service in emergency
situations. In addition, the analytical technique should
allow for determination of pediatric samples using the
minimum possible sample size; 30 L serum or less.
Analytical techniques vary according to different
laboratory requirements and hospital budgets. Many
automated chemistry instruments used for biochemical
analysis have drug detection kits that can be added to
their menus. Most laboratories use immunoassay
methods for TDM service. One of the most popular
bench-top assay instruments is the fluorescence
polarization immunoassay (FPIA) by Abbot
Diagnostics, commonly known as the TDx® method.
Another immunoassay is the enzyme multiplied
immunoassay technique (EMIT®), currently marketed
by Siemens Healthcare Diagnostics. The instruments
and software of these assay techniques may have
undergone continuous upgrading but the principles of
assay determination remain the same.
For some drugs, chromatographic techniques such
as gas chromatography (GC) and high performance
liquid chromatography (HPLC) may be used. Unlike
immunoassays, chromatographic techniques do not
depend on commercially available reagent kits. GC and
HPLC are considered the gold standard for specificity,
and they have the advantage of being able to
simultaneously detect the parent drug and its
metabolites. These techniques are more suitable for
research institution and are not usually used for routine
measurement in patient care settings.
The laboratory that is involved in the TDM service
must ensure that appropriate quality control is
undertaken. This includes having internal and external
quality control programs. All quality control parameters
should be documented and assessed regularly by the
clinical chemist. The laboratory technologist or clinical
chemist should be aware of analytical interferences
and artifacts, which may lead to falsely high or low
concentrations of drugs [14-17].
Different methods of analysis may give different
values for a given sample due to differences in their
specificities. A parent drug may cross react with its
metabolites, thus giving a higher concentration value.
For this reason, when an assay is requested for
cyclosporine A (CSA), the clinical chemist must report
the method used for analysis because the reference
range of CSA depends on the method used.
Batch Versus Individual Assay Determination
In general, SDC is expensive relative to other
routine biochemical analysis. Efforts should be done to
provide a good service at reasonable coast. Consider
performing sample assay in batches whenever possible
and select an analytical tool that is most suitable to the
work load.
Type of Sample
The type of sample will vary according to the
specific assay. Most assays allow serum, some require
plasma, and for some assays either is acceptable.
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. Some assays are
specific about storage of samples. Plastic cryo-vial type
tubes are acceptable for most assays. For CSA, some
methods specifically require whole blood, not plasma,
collected in an EDTA tube. Analytical methods may be
affected by temperature and all these variables should
be standardized.
2.4. Appropriate Interpretation of Results
Serum drug concentration without proper
interpretation of its value could be misleading.
Therefore, drug concentration determinations must
Figure 2: Peak and trough levels of gentamicin (assuming
once daily dose of 5 mg/kg and normal renal function in
adults).

5. Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 2 91
always be interpreted in the context of the clinical data.
Some of the key points regarding appropriate
interpretation include the following [13].
(a) Comprehensive knowledge of variables
affecting the pharmacokinetic and pharmacodynamic
characteristics of the drug being monitored.
Active metabolite: Some monitored drugs are
biotransformed into compounds that are
pharmacologically active. When evaluating the
therapeutic effect of such drugs, the relative
contributions of all active substances present in the
serum must be considered e.g. carbamazepine is
biotransformed to the active metabolite
carbamazepine-10,11-epoxide.
Disease states: Acute or chronic disease alters drug
clearance patterns. For example, severe liver disease
impairs the clearance of most antiepileptic drugs.
Congestive cardiac failure can cause elevated drug
concentrations of drugs dependent on hepatic
metabolism for clearance. Patient with severe renal
impairment has lower albumin concentration and hence
high free concentration of phenytoin.
Age: Variability in pharmacokinetic parameters and
clinical response to drugs occurs at extremes of age.
For example, neonates during the first week have
larger volume of distribution and longer half life of
aminoglycosides compared to children. They also have
altered metabolic pathway of theophylline and
neonates with birth asphyxia show marked reduction in
Phenobarbital clearance.
Pregnancy: A number of patients report an increase
in seizure frequency during pregnancy, which can be
attributed to behavioral factors, physical changes,
pharmacokinetic alterations of antiepileptic drugs, and
natural fluctuations of seizure frequency [18]. Examples
of pharmacokinetic influence include changes in
phenytoin absorption or metabolism. Periodic
measurement of serum phenytoin concentrations is
particularly valuable in the management of a pregnant
epileptic patient as a guide to an appropriate
adjustment of dosage. SDC may return to pre-
pregnancy values after delivery, therefore, postpartum
restoration of the original dosage will probably be
indicated.
Other variables: Factors like smoking, stress, drug
formulation (generic versus trade name), drug-drug or
drug-food interaction, environmental factors, and
circadian effect can alter pharmacokinetic properties of
the drug being measured.
(b) Knowledge of relevant clinical response and
laboratory investigation. Examples of common
monitoring parameters are shown in Tables 3 and 4.
Table 3: Examples of Investigations and Clinical Observations [5]
Investigation Comment
skin, hair, gum, eye Signs of adverse effects. (e.g. phenytoin)
Culture and sensitivity To ensure proper selection of the antibiotic; design optimal regimen
Forced expiratory volume in one second (FEV1), Peak expiratory
flow rate (PEFR), Arterial blood gas (ABG)
Markers for efficacy of bronchodilators (e.g. Theophylline)
ECG abnormality, nausea, vomiting, headache Signs of adverse effects (e.g. digoxin toxicity)
Table 4: Examples of Biochemical and Hematological Parameters [5]
Biochemical and hematological parameter Drug Comment
Renal function tests (e.g. SCr) Aminoglycosides and Vancomycin Indication of nephrotoxicity or reduced
elimination
Liver function tests (e.g. AST, ALT) Valproic acid and Acetaminophen Marker for liver toxicity
Serum electrolytes (e.g. K
+
) Digoxin Enhance cardiac toxicity of digoxin
Complete blood count (e.g. abnormal progressive
low RBC)
Carbamazepine Marker for aplastic anemia
Thyroid function tests (e.g. T3 and T4) Digoxin Altered response in hypothyroidism
or hyperthyroidism

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C-TDM Request Form
It is essential to design a request form specific for
TDM [19]. It is important the request form contains all
relevant information in order to accurately interpret the
results. However, it may not be possible to include
every piece of information in the form. Sometimes the
information can be obtained from the patient’s medical
records. In addition, the clinical pharmacist/
pharmacologist still has the duty to monitor and discuss
patient’s clinical response with the clinician.
Dosing and sampling times must be accurately
documented in the patient’s medical records and in the
TDM form. It can be difficult to make sense of a result
unless collection time and previous last dose is known.
For example, an elevated digoxin concentration may be
due to the sample being taken too early after the last
dose when the drug is still in its distributive phase. It is
important to note how long the person has been on the
drug, to ascertain that the drug has achieved a steady-
state condition. It is also useful to include on the
request form any co-morbidities or other notes (e.g.
pregnancy) that would assist in the interpretation of the
TDM results.
Information required on TDM request form [5]
Patient demography
Name of patient-
Patient hospital number (registration number)
Ward or unit
Age, weight, height, gender, race
Smoking and alcohol consumption
Pregnancy
Gender
Relevant Clinical Summary of Patient (including
indication of drug and concurrent medical problems)
Laboratory indices and concurrent drugs (including
renal function tests, liver function tests, and serum
electrolytes)
Information on drug requested
Name of drug requested for TDM
Date started
Dose regimen (including dose, frequency and route)
Date and time last dose given/taken
Information on sample
Sampling time
Indications for testing
To confirm suspected toxicity
To rule out non-compliance
To rule out therapeutic failure (e.g. patient not
responding to treatment)
To obtain baseline value (e.g. Before pregnancy)
Other indications ….
Name of requesting clinician and signature
Date of request
2.5. Other Considerations in TDM Service
(a) Recognize the Flexible Nature of the Reference
Range
Reference ranges for commonly monitored drugs
are available in many TDM handbooks. They must be
used as a guide rather than absolute values. The
following points are provided to illustrate this fact.
The target peak of gentamicin depends on severity,
site of infection, and immune status of the patient. For
example, urinary tract infections can be treated with
lower SDC compared to pseudomonal pneumonia.
Sometimes the reference range depends on drug
indication. For example, theophylline (10 to 20 mg/L)
for bronchial asthma and 5 to 10 mg/L for apnea of
prematurity. Therefore, it is important to state in the
TDM request form the indication of the drug.
Drug concentrations within the usual reference
range do not rule out drug toxicity in a given patient.
For example, physiologic variables like hypokalemia
can increase the risk of digoxin toxicity.
Many adverse effects are dose-independent (or not
related to SDC). For example, gum hyperplasia
associated with phenytoin and aplastic anemia
produced by carbamazepine.
Many factors alter the effect of a drug concentration
at the site of action. For example, SDC of phenytoin

7. Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 2 93
that is within the reference range may be associated
with dose-related adverse effects in patients with very
low albumin level.
Consider the synergistic or additive effect of drugs.
For example, a lower carbamazepine SDC may be
desired when used with some other antiepileptic drugs.
In certain life threatening situations, higher than
normal concentrations may be required or even
recommended. For example, phenobarbital SDC of 200
umol/L (normal range 40 to 170 umol/L) may be
acceptable in severe seizures in neonates provided the
vital signs are normal.
(b) Recognize Abnormal Results
Abnormal or unexpected results are not uncommon
in TDM. Possible causes of unusual or unexpected
TDM results may arise from problems with
bioavailability, drug interactions, non-compliance or
medication errors. For example, unexpected high
gentamicin level in a patient with normal renal function.
The most common causes of unexpected serum
concentrations are
Sampling time error. This is common for antibiotics
Sample mix-up. e.g. peak/trough concentrations for
gentamicin
Samples contaminated with the injected drug (e.g
vancomycin) during sample withdrawal usually give
very high SDC.
Other possible reasons include inappropriate
dosage, generic or different brand product interchange,
poor bioavailability, drug or food interactions, acute
hepatic or renal dysfunction, altered protein binding
and genetic factors.
(c) Knowledge of Appropriate Procedure for
Management of Overdose and Toxicity
Measurement of SDC in case of overdose or toxicity
requires knowledge of how the results are going to be
used in management of these conditions. For example,
SDC can be used to estimate appropriate dose of Fab
digoxin antibody in severe digoxin toxicity. Based on
the SDC obtained and an appropriate assumption of
patient’s volume of distribution, the amount of digoxin
in the body can be estimated. Therefore, the
corresponding amount of Fab antibody can be
calculated and administered. Another example is the
measurement of SDC of acetaminophen in acute
poisoning. The need to administer N-acetylcysteine is
based on the probability of developing hepatotoxicty
based on the Rumack-Matthew nomogram.
(d) Education
Continuous education program regarding TDM is
important to ensure all health professionals are aware
of the basic principles and to ensure effective
implementation of the service in clinical setting.
Strategies for physician education regarding optimal
use of TDM include traditional and non-traditional
education approaches [20, 21]. In general, most
traditional educational approaches are effective at
changing physician behavior in the short term,
however, these approaches are labor-intensive and
their effect has waned with time.
In view of the experiences with TDM services in
Saudi Arabia, Egypt and Malaysia, we suggest to
include basic principles of TDM in undergraduate
courses for medical, nursing, and medical technology
students as an effective tool for optimization of TDM
service in developing countries. Recently, e-learning
methodology (software provided as CDs) has been
suggested as a tool for supporting clinicians to
understand the pharmacology and pharmacokinetics
relevant to drugs being monitored. This approach has
been shown to be useful because most clinical
professionals work in a busy environment and are often
faced with restrictions due to time or other factors. E-
learning, therefore, allows them pursue their studies at
their own pace [21].
(e) Patient Education
Patients should be educated on the importance of
complying with their physician's orders for medications,
and should be told to report any complications or side
effects they may experience. Patients should also be
told about the frequency of their drug monitoring tests,
and why keeping their appointment is important.
Patient education can increase the accuracy of
sampling time. At King Abdulaziz University Hospital,
patients have been provided with printed instructions.
(f) Research
Research in TDM improves the utilization of service
in clinical practice. Relevant researches cover include
optimization of TDM in certain population or clinical
situation such as in preterm neonates, children,
transplant patients and cystic fibrosis patients [22-25].

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(g) Computerization of TDM Service
Computerization can simplify complex procedures
and avoid errors associated with missing
documentation. Guided dose algorithms can be
implemented for many drugs for which TDM is
required, taking into account patient-specific factors
such as age, gender, weight, interacting drugs, and
major organ functions. Various pharmacokinetic
software are available in the market. These algorithms
can also suggest monitoring of drugs at appropriate
times. Computerization allows the availability of clinical
data at an instant. Data such as drug regimen, dosing
times, and sampling times would be available when
requested. When the system is integrated with other
laboratory services, the clinical pharmacist/
pharmacologist can use these biochemical data to help
make a decision.
3. SUMMARY
Measurement of serum drug concentration without
appropriate interpretation is useless or even
misleading.
Efforts should be implemented to insure cost-
effective service. The following criteria are suggested:
Clear indication for the drug level determination
Insure optimal sampling time;
appropriate analytical techniques;
appropriate interpretation of results. in view of relevant
biochemical and hematological parameters and clinical
observations.
Reference range is considered as guide rather than
an absolute value, i.e. some patients may require and
tolerate higher level while others show good clinical
response with lower level.
TDM specialist should be aware of appropriate
procedure for management of overdose and toxicity.
Continuous education for patients and staff as well
as research are also important tools to develop the
TDM practice.
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Received on 15-04-2013 Accepted on 03-06-2013 Published on 30-12-2013
DOI: http://dx.doi.org/10.14205/2309-4435.2013.01.02.5
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