ELPHAS SHIKOKOTI SIAYI BSC MLS
Therapeutic drug monitoring
Definition of terms
Therapeutic drug monitoring (TDM): refers to the laboratory measurement of a drug
concentration which, with appropriate interpretation, will directly influence prescribing procedures
and ensure the patient maintains a concentration of drug within a target range (therapeutic range,
therapeutic window).
Steady State – Represents the equilibrium between the amount of drug given and the amount
eliminated over the dosing interval. In general it takes a drug four to five half-lives to reach a
steady state. Sampling should occur when the drug has reached its steady state to judge efficacy
and toxicity of the drug therapy. Steady State Concentration (CSS) – blood drug or metabolite
concentrations during a dosing interval after a steady state has been achieved. Steady state
concentrations fluctuate between a maximum (peak) and minimum (trough) concentration with
each dosing interval.
Therapeutic Range – Range of drug concentrations associated with high degree of efficacy and
low risk of dose-related toxicity in majority of patients.
Trough Serum Concentration – The lowest drug concentration during a dosing interval when drug
is given intermittently. The trough concentration generally occurs immediately before
administration of the next dose.
Total Drug Concentration – The sum of unbound and bound drug in serum or plasma.
Unbound Drug Concentration – The concentration of drug in serum nd plasma that is free and
not bound to proteins. The unbound drug concentration in serum is more closely associated with
drug response than total drug concentrations.
Loading Dose – Dose(s) of drugs given at the onset of therapy to rapidly provide a therapeutic
effect. Use of a loading dose prior to a maintenance dosage regimen will shorten the time required
to approach a steady state.
1
,Historical development of TDM
The science of Therapeutic Drug Monitoring grew out of the recognition that:
- Certain drugs have a narrow therapeutic range
- In concentrations above the upper limit of the range,the drug can be toxic
- In concentrations below the lower limit of the range,the drug can be ineffective
- Not all patients have the same response at similar doses
These findings led to the development of Clinical Pharmacology departments, whose job it was
both to provide the testing and to perform the studies needed to determine the therapeutic ranges
and factors that affect results generation and interpretation. Today there are over 20 therapeutic
drugs which are routinely monitored.
Aim of therapeutic drug monitoring
The goal of therapeutic drug monitoring is to optimize the drug dose so that the patient’s drug
concentrations remain within the therapeutic range for the drug.
Common Indications for TDM Testing
Therapeutic drug monitoring is indicated if:
▪ drug efficacy is difficult to establish clinically e.g phenytoin
▪ toxicity is suspected
▪ inadequate therapeutic response
▪ there is non-compliance concerns
▪ there is need for dosage change
▪ there is change in patient’s clinical state
▪ there is change in co-medications (quinidine decreases digoxin clearance)
▪ the manifestations of drug toxicity and disease state are similar (theophylline)
TDM is not indicated if:
▪ Toxicity is not a realistic concern (Penicillin)
▪ Effects can be measured using functional laboratory tests (Anticoagulants)
▪ Plasma concentration is not predictably related to effects (Anticoagulants) ▪ Effect of the
relationship remains undefined (Antidepressants)
2
, Samples for analysis
Usually, plasma or serum is used for drug analysis, depending on the equipment used. However,
with cyclosporin there are large shifts of drug between red cells and plasma occur with storage and
temperature change and for these reason whole blood is assayed. Some blood collecting tubes,
especially those containing a particular anticoagulant or a gel to separate cells and plasma, may
not be suitable for all drugs due to drug adsorption by the gel or other components in the tube. For
example lithium heparin is an inappropriate anticoagulant for lithium samples and certain gel
separator tubes should be avoided for some drugs such as phenytoin. In small babies capillary
blood samples are collected for TDM. Urine, CSF and saliva are also biological samples although
not commonly used.
Timing of sampling
The correct time of sampling is important. Drug concentrations vary over the dosing interval and
with the duration of dosing in relation to achieving a steady state. The least variable point in the
dosing interval is the pre-dose or trough concentration. For drugs with short half-lives in relation
to the dosing interval, samples should be collected pre-dose. For drugs with long half-lives such
as phenytoin, phenobarbitone or amiodarone, samples collected at any point in the dosage interval
can be satisfactory. For digoxin, any point after the distribution phase (after 6 hours post-dose is
acceptable. Allowance should be made if samples are taken at other points in the dosage interval.
The steady state is determined by the half-life and the use, or not, of a loading dose. It is usually
best to wait and assay at steady state unless there are concerns about toxicity. This does not apply
to drugs such as amiodarone and perhexiline with very long half-lives and which can cause severe
toxicity - steady state may take months to be reached and dose adjustments need to be made along
the way. With all drugs, if a sample is taken before steady state is reached, allowance needs to be
made for this in interpreting the concentration.
Analytical methods in TDM
Drug assay methods should have adequate sensitivity, be specific for the drug (or metabolite) to be
measured and have appropriate accuracy and precision. Most high-volume drug assays are now
carried out by automated immunoassay methods which have these characteristics. However, a
number continue to require manual assay by methods such as high performance liquid
chromatography (HPLC) and gas liquid chromatography (GLC) (e.g. amiodarone, perhexiline).
3
Therapeutic drug monitoring
Definition of terms
Therapeutic drug monitoring (TDM): refers to the laboratory measurement of a drug
concentration which, with appropriate interpretation, will directly influence prescribing procedures
and ensure the patient maintains a concentration of drug within a target range (therapeutic range,
therapeutic window).
Steady State – Represents the equilibrium between the amount of drug given and the amount
eliminated over the dosing interval. In general it takes a drug four to five half-lives to reach a
steady state. Sampling should occur when the drug has reached its steady state to judge efficacy
and toxicity of the drug therapy. Steady State Concentration (CSS) – blood drug or metabolite
concentrations during a dosing interval after a steady state has been achieved. Steady state
concentrations fluctuate between a maximum (peak) and minimum (trough) concentration with
each dosing interval.
Therapeutic Range – Range of drug concentrations associated with high degree of efficacy and
low risk of dose-related toxicity in majority of patients.
Trough Serum Concentration – The lowest drug concentration during a dosing interval when drug
is given intermittently. The trough concentration generally occurs immediately before
administration of the next dose.
Total Drug Concentration – The sum of unbound and bound drug in serum or plasma.
Unbound Drug Concentration – The concentration of drug in serum nd plasma that is free and
not bound to proteins. The unbound drug concentration in serum is more closely associated with
drug response than total drug concentrations.
Loading Dose – Dose(s) of drugs given at the onset of therapy to rapidly provide a therapeutic
effect. Use of a loading dose prior to a maintenance dosage regimen will shorten the time required
to approach a steady state.
1
,Historical development of TDM
The science of Therapeutic Drug Monitoring grew out of the recognition that:
- Certain drugs have a narrow therapeutic range
- In concentrations above the upper limit of the range,the drug can be toxic
- In concentrations below the lower limit of the range,the drug can be ineffective
- Not all patients have the same response at similar doses
These findings led to the development of Clinical Pharmacology departments, whose job it was
both to provide the testing and to perform the studies needed to determine the therapeutic ranges
and factors that affect results generation and interpretation. Today there are over 20 therapeutic
drugs which are routinely monitored.
Aim of therapeutic drug monitoring
The goal of therapeutic drug monitoring is to optimize the drug dose so that the patient’s drug
concentrations remain within the therapeutic range for the drug.
Common Indications for TDM Testing
Therapeutic drug monitoring is indicated if:
▪ drug efficacy is difficult to establish clinically e.g phenytoin
▪ toxicity is suspected
▪ inadequate therapeutic response
▪ there is non-compliance concerns
▪ there is need for dosage change
▪ there is change in patient’s clinical state
▪ there is change in co-medications (quinidine decreases digoxin clearance)
▪ the manifestations of drug toxicity and disease state are similar (theophylline)
TDM is not indicated if:
▪ Toxicity is not a realistic concern (Penicillin)
▪ Effects can be measured using functional laboratory tests (Anticoagulants)
▪ Plasma concentration is not predictably related to effects (Anticoagulants) ▪ Effect of the
relationship remains undefined (Antidepressants)
2
, Samples for analysis
Usually, plasma or serum is used for drug analysis, depending on the equipment used. However,
with cyclosporin there are large shifts of drug between red cells and plasma occur with storage and
temperature change and for these reason whole blood is assayed. Some blood collecting tubes,
especially those containing a particular anticoagulant or a gel to separate cells and plasma, may
not be suitable for all drugs due to drug adsorption by the gel or other components in the tube. For
example lithium heparin is an inappropriate anticoagulant for lithium samples and certain gel
separator tubes should be avoided for some drugs such as phenytoin. In small babies capillary
blood samples are collected for TDM. Urine, CSF and saliva are also biological samples although
not commonly used.
Timing of sampling
The correct time of sampling is important. Drug concentrations vary over the dosing interval and
with the duration of dosing in relation to achieving a steady state. The least variable point in the
dosing interval is the pre-dose or trough concentration. For drugs with short half-lives in relation
to the dosing interval, samples should be collected pre-dose. For drugs with long half-lives such
as phenytoin, phenobarbitone or amiodarone, samples collected at any point in the dosage interval
can be satisfactory. For digoxin, any point after the distribution phase (after 6 hours post-dose is
acceptable. Allowance should be made if samples are taken at other points in the dosage interval.
The steady state is determined by the half-life and the use, or not, of a loading dose. It is usually
best to wait and assay at steady state unless there are concerns about toxicity. This does not apply
to drugs such as amiodarone and perhexiline with very long half-lives and which can cause severe
toxicity - steady state may take months to be reached and dose adjustments need to be made along
the way. With all drugs, if a sample is taken before steady state is reached, allowance needs to be
made for this in interpreting the concentration.
Analytical methods in TDM
Drug assay methods should have adequate sensitivity, be specific for the drug (or metabolite) to be
measured and have appropriate accuracy and precision. Most high-volume drug assays are now
carried out by automated immunoassay methods which have these characteristics. However, a
number continue to require manual assay by methods such as high performance liquid
chromatography (HPLC) and gas liquid chromatography (GLC) (e.g. amiodarone, perhexiline).
3
