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Basic Principles of Therapeutic Drug Monitoring

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 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, 1, 1-9 1

Basic Principles of Therapeutic Drug Monitoring

Ahmed S. Ali1,*, Osman Hassa Osman1, Ab Fatah Ab Rahman2 and

Mahran Shake Ahmed3

1
Faculty of Medicine King Abdul-Aziz University, Saudi Arabia
2
Faculty of Pharmacy, TIBA 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 chapter summarize the criteria to insure optimal TDM service.

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,
1. INTRODUCTION
(2) Knowledge of pharmacological and
pharmacokinetic profiles of the administered
Therapeutic drug monitoring (TDM) has contributed
drugs,
substantially in assisting patient management and has
become an important tool in clinical medicine. The (3) Knowledge of relevant patient’s profile like
provision of TDM service requires a team effort from demographic data, clinical status, laboratory and
various clinical services. In a typical TDM service, the other clinical investigations, and
clinician will determine the initial dose of a drug. A
clinical pharmacist assists by providing essential (4) Interpretation of SDC after taking into
information about the drug, revises the initial regimen if consideration all of the above information and
necessary, and provides a plan for TDM. A nurse or a individualizing drug regimen according to the
phlebotomist collects the blood sample at an clinical needs of the patient.
appropriate time. The nurse usually documents
essential information and clinical response of the TDM when used properly helps to improve efficacy
patient. Finally, a clinical laboratory scientist or chemist and minimize toxicity of selected drugs especially those
performs the drug assays (Figure 1). Once the assay 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
*Address correspondence to this author at the Faculty of Medicine King Abdul-
Aziz University, Saudi Arabia; E-mail: ahmedali@gmail.com 2.

© 2013 Pharma Professional Services

2 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 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
Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 3

2. OPTIMIZATION OF TDM SERVICE 2.2. Optimal Sampling Time

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

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].
Figure 2: Peak and trough concentrations of gentamicin Different methods of analysis may give different
(Hypthetical level designed by the authors).
values for a given sample due to differences in their
specificities. A parent drug may cross react with its
2.3. Laboratory Considerations
metabolites, thus giving a higher concentration value.
Analytical Techniques For this reason, when an assay is requested for
cyclosporine A (CSA), the clinical chemist must report
The analytical method should be sensitive, precise, the method used for analysis because the reference
accurate, and specific enough to measure SDC within range of CSA depends on the method used.
the reference range. It should allow rapid analysis to
ensure the provision of TDM service in emergency Batch Versus Individual Assay Determination
situations. In addition, the analytical technique should In general, SDC is expensive relative to other
allow for determination of pediatric samples using the routine biochemical analysis. Efforts should be done to
minimum possible sample size; 30
L serum or less. provide a good service at reasonable coast. Consider
performing sample assay in batches whenever possible
Analytical techniques vary according to different
and select an analytical tool that is most suitable to the
laboratory requirements and hospital budgets. Many work load.
automated chemistry instruments used for biochemical
analysis have drug detection kits that can be added to Type of Sample
their menus. Most laboratories use immunoassay
The type of sample will vary according to the
methods for TDM service. One of the most popular
specific assay. Most assays allow serum, some require
bench-top assay instruments is the fluorescence plasma, and for some assays either is acceptable.
polarization immunoassay (FPIA) by Abbot Samples should be collected and centrifuged as soon
Diagnostics, commonly known as the TDx® method. as possible. Avoid serum-separator tubes because
Another immunoassay is the enzyme multiplied these may lower drug concentrations due to the
immunoassay technique (EMIT®), currently marketed adsorption of drug into the matrix. Some assays are
by Siemens Healthcare Diagnostics. The instruments specific about storage of samples. Plastic cryo-vial type
and software of these assay techniques may have tubes are acceptable for most assays. For CSA, some
undergone continuous upgrading but the principles of methods specifically require whole blood, not plasma,
assay determination remain the same. collected in an EDTA tube. Analytical methods may be
affected by temperature and all these variables should
For some drugs, chromatographic techniques such be standardized.
as gas chromatography (GC) and high performance
liquid chromatography (HPLC) may be used. Unlike 2.4. Appropriate Interpretation of Results
immunoassays, chromatographic techniques do not
depend on commercially available reagent kits. GC and Serum drug concentration without proper
HPLC are considered the gold standard for specificity, interpretation of its value could be misleading.
and they have the advantage of being able to Therefore, drug concentration determinations must
simultaneously detect the parent drug and its always be interpreted in the context of the clinical data.
metabolites. These techniques are more suitable for Some of the key points regarding appropriate
interpretation include the following [13].
Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 5

(a) Comprehensive knowledge of variables Pregnancy: A number of patients report an increase

affecting the pharmacokinetic and pharmacodynamic in seizure frequency during pregnancy, which can be
characteristics of the drug being monitored. attributed to behavioral factors, physical changes,
pharmacokinetic alterations of antiepileptic drugs, and
Active metabolite: Some monitored drugs are natural fluctuations of seizure frequency [18]. Examples
biotransformed into compounds that are of pharmacokinetic influence include changes in
pharmacologically active. When evaluating the phenytoin absorption or metabolism. Periodic
therapeutic effect of such drugs, the relative measurement of serum phenytoin concentrations is
contributions of all active substances present in the particularly valuable in the management of a pregnant
serum must be considered e.g. carbamazepine is epileptic patient as a guide to an appropriate
biotransformed to the active metabolite adjustment of dosage. SDC may return to pre-
carbamazepine-10,11-epoxide. pregnancy values after delivery, therefore, postpartum
restoration of the original dosage will probably be
Disease states: Acute or chronic disease alters drug
indicated.
clearance patterns. For example, severe liver disease
impairs the clearance of most antiepileptic drugs. Other variables: Factors like smoking, stress, drug
Congestive cardiac failure can cause elevated drug formulation (generic versus trade name), drug-drug or
concentrations of drugs dependent on hepatic drug-food interaction, environmental factors, and
metabolism for clearance. Patient with severe renal circadian effect can alter pharmacokinetic properties of
impairment has lower albumin concentration and hence the drug being measured.
high free concentration of phenytoin.
(b) Knowledge of relevant clinical response and
Age: Variability in pharmacokinetic parameters and laboratory investigation. Examples of common
clinical response to drugs occurs at extremes of age. monitoring parameters are shown in Tables 3 and 4.
For example, neonates during the first week have high
volume of distribution of aminoglucoside and long half C-TDM Request Form
lives. They also have altered metabolic pathway of It is essential to design a request form specific for
theophylline and neonates with birth asphyxia show TDM [19]. It is important the request form contains all
marked reduction in Phenobarbital clearance. relevant information in order to accurately interpret the

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 Markers for efficacy of bronchodilators (e.g. Theophylline)
flow rate (PEFR), Arterial blood gas (ABG)
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 Carbamazepine Marker for aplastic anemia
low RBC)
Thyroid function tests (e.g. T3 and T4) Digoxin Altered response in hypothyroidism
or hyperthyroidism
6 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 Ali et al.

results. However, it may not be possible to include Information on sample

every piece of information in the form. Sometimes the
information can be obtained from the patient’s medical Date and time sample taken
records. In addition, the clinical pharmacist/
Indications for testing
pharmacologist still has the duty to monitor and discuss
patient’s clinical response with the clinician. To confirm suspected toxicity
Dosing and sampling times must be accurately To rule out non-compliance
documented in the patient’s medical records and in the
TDM form. It can be difficult to make sense of a result To rule out therapeutic failure (e.g. patient not
unless collection time and previous last dose is known. responding to treatment)
For example, an elevated digoxin concentration may be
due to the sample being taken too early after the last To obtain baseline value (e.g. Before pregnancy)
dose when the drug is still in its distributive phase. It is
Other indications ….
important to note how long the person has been on the
drug, to ascertain that the drug has achieved a steady- Name of requesting clinician and signature
state condition. It is also useful to include on the
request form any co-morbidities or other notes (e.g. Date of request
pregnancy) that would assist in the interpretation of the
TDM results. 2.5. Other Considerations in TDM Service

Information required on TDM request form [5] (a) Recognize the Flexible Nature of the Reference
Range
Patient demography
Reference ranges for commonly monitored drugs
Name of patient- are available in many TDM handbooks. They must be
used as a guide rather than absolute values. The
Patient hospital number (registration number) following points are provided to illustrate this fact.

Ward or Unit or Clinic The target peak of gentamicin depends on severity,

site of infection, and immune status of the patient. For
Age, weight, height, gender, race example, urinary tract infections can be treated with
lower SDC compared to pseudomonal pneumonia.
Smoking and alcohol consumption
Sometimes the reference range depends on drug
Pregnancy indication. For example, theophylline (10 to 20 mg/L)
for bronchial asthma and 5 to 10 mg/L for apnea of
Gender
prematurity. Therefore, it is important to state in the
Relevant Clinical Summary of Patient (including TDM request form the indication of the drug.
indication of drug and concurrent medical problems)
Drug concentrations within the usual reference
Laboratory indices and concurrent drugs (including range do not rule out drug toxicity in a given patient.
renal function tests, liver function tests, and serum For example, physiologic variables like hypokalemia
electrolytes) can increase the risk of digoxin toxicity.

Information on drug requested Many adverse effects are dose-independent (or not
related to SDC). For example, gum hyperplasia
Name of drug requested for TDM associated with phenytoin and aplastic anemia
produced by carbamazepine.
Date started
Many factors alter the effect of a drug concentration
Dose regimen (including dose, frequency and route) at the site of action. For example, SDC of phenytoin
that is within the reference range may be associated
Date and time last dose given/taken
with dose-related adverse effects in patients with very
low albumin level.
Basic Principles of Therapeutic Drug Monitoring Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 7

Consider the synergistic or additive effect of drugs. (d) Education

For example, a lower carbamazepine SDC may be Continuous education program regarding TDM is
desired when used with some other antiepileptic drugs. important to ensure all health professionals are aware
of the basic principles and to ensure effective
In certain life threatening situations, higher than
implementation of the service in clinical setting.
normal concentrations may be required or even
Strategies for physician education regarding optimal
recommended. For example, phenobarbital SDC of 200
use of TDM include traditional and non-traditional
umol/L (normal range 40 to 170 umol/L) may be
education approaches [20, 21]. In general, most
acceptable in severe seizures in neonates provided the
traditional educational approaches are effective at
vital signs are normal.
changing physician behavior in the short term, but the
(b) Recognize Abnormal Results problem has been that these approaches are labor-
intensive and their effect has waned with time
Abnormal or unexpected results are not uncommon
in TDM. Possible causes of unusual or unexpected In view of the experiences with TDM services in
TDM results may arise from problems with Saudi Arabia and Egypt, we suggest to include basic
bioavailability, drug interactions, non-compliance or principles of TDM in undergraduate courses for
medication errors. For example, a high gentamicin medical, nursing, and medical technology students as
trough or digoxin or vancomycin concentration can an effective tool for optimization of TDM service in
occur in a patient with normal renal when previous developing countries. Recently, e-learning
concentration is normal. methodology (software provided as CDs) has been
suggested as a tool for supporting clinicians to
The most common causes of unexpected serum
understand the pharmacology and pharmacokinetics
concentrations are
relevant to drugs being monitored. This approach has
Sampling time error. This is common for antibiotics been shown to be useful because most clinical
professionals work in a busy environment and are often
Sample mix-up. e.g. peak/trough concentrations for faced with restrictions due to time or other factors. E-
gentamicin learning, therefore, allows them pursue their studies at
their own pace (Samani, 2009).[21]
Contaminated sample; usually abnormally high SDC.
(e) Patient Education
Other possible reasons include inappropriate
Patients should be educated on the importance of
dosage, generic or different brand product interchange,
complying with their physician's orders for medications,
poor bioavailability, drug or food interactions, acute
and should be told to report any complications or side
hepatic or renal dysfunction, altered protein binding
effects they may experience. Patients should also be
and genetic factors.
told about the frequency of their drug monitoring tests,
(c) Knowledge of Appropriate Procedure for and why keeping their appointment is important.
Management of Overdose and Toxicity Patient education can increase the accuracy of
sampling time. At King Abdulaziz University Hospital,
Measurement of SDC in overdose and toxicity
patients have been provided with printed instructions.
cases requires knowledge of how the results are going
to be used in its management. For example, SDC can (f) Research
be used to estimate appropriate dose of Fab digoxin
Research in TDM improves the utilization of service
antibody in severe digoxin toxicity. Based on the SDC
in clinical practice. Relevant researches cover include
obtained and an appropriate assumption of patient’s
optimization of TDM in certain population or clinical
volume of distribution, the amount of digoxin in the
situation such as in preterm neonates, children,
body can be estimated. Therefore, the corresponding
transplant patients and cystic fibrosis patients [22-25].
amount of Fab antibody can be calculated and
administered. Another example is the measurement of (g) Computerization of TDM Service
SDC of acetaminophen in acute poisoning. The need to
administer N-acetylcysteine is based on the probability Computerization can simplify complex procedures
of developing hepatotoxicty based on the Rumack- and avoid errors associated with missing
Matthew nomogram. documentation. Guided dose algorithms can be
implemented for many drugs for which TDM is
8 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 Ali et al.

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