TDM will be useful if:

• Appropriate analytic techniques are available to

determine the drug and metabolite levels
• Large individual variability in steady state plasma
concentration exits at any given dose
• The therapeutic effect can not be readily assessed by
the clinical observation
• A direct relationship exists between the drug or drug
metabolite levels in plasma and the pharmacological or
toxic effects
• The drug in question has a narrow therapeutic range
 TDM INDICATION FOR DRUGS
• Prevention of adverse drug effects
• Major organ failure
• Wide variation in the metabolism of drugs
• Drugs with saturable metabolism
• Therapeutic failure
• Non compliance
• Poorly defined clinical end point
• Low therapeutic index
1. \
 Why Levels Monitored
• Not all patients have the same response at
similar doses.
• In concentrations below the lower limit of the
range, the drug can be ineffective .
• In concentrations above the upper limit of the
range, the drug can be toxic .
• Certain drugs have a narrow therapeutic
range
2. When there is a narrow concentration interval between therapeutic
and toxic effects The therapeutic index (therapeutic ratio, toxic-
therapeutic ratio) for a drug indicates the margin between the
therapeutic dose and the toxic dose: the larger, the better.
• For most patients (with the exception of those who are
hypersensitive) penicillin has a very high therapeutic ratio. It is safe to
use in much higher doses than necessary to treat the patient
satisfactorily, with no necessity to check the concentration attained.
• However, for other drugs (eg, anticoagulants, aminoglycoside
antibiotics, anti-neoplastic drugs, immunosuppressants, cardiac
glycosides) the margin between desirable and toxic dose is very small
and monitoring is valuable in achieving effective concentrations
without systemic toxicit
• In general, the cost of measuring drug concentrations is greater than for routine
clinical chemical estimations, and to use expensive facilities to produce
‘numbers’ resulting from analysis of samples taken at random from patients
described only by name or number is meaningless and misleading, as well as
being a waste of money.
• Analytical techniques of high specificity (often relying on high-performance
liquid chromatography (HPLC), or mass spectroscopy or radioimmunoassay)
avoid the pitfalls of less specific methods which may detect related compounds
(e.g. drug metabolites).
• Even so, quality control monitoring of anticonvulsant analyses performed by
laboratories both in the UK and in the USA have revealed that repeated analyses
of a reference sample can produce some startlingly different results.
• The most important principle for the clinician is that plasma drug concentrations
must always be interpreted in the context of the patient’s clinical state.
• The most reproducible time to take measurements is immediately
pre-dose (trough concentration), when the lowest levels in the cycle
will be obtained. This is best if an indication of drug efficacy is
required. This sample will show least between-sample variability in
patients on chronic therapy.
• The use of peak and trough concentrations for detecting toxicity of
aminoglycoside antibiotics has become less relevant with once-daily
dosing regimens, but sampling at two hours post dose for
cyclosporine has become a common and effective TDM technique.
This type of sampling in the absorption/distribution phase is highly
sensitive to accurate determination of sampling time in relation to
dose. The average steady state concentration may be obtained by
taking samples approximately midway between doses.
• Daily monitoring may be necessary in critically ill patients with rapidly
changing clearance, for example with aminoglycoside antibiotics.
• Dosage requirements for immunosuppressive drugs vary markedly in
the early days and weeks post-transplantation, and frequent
monitoring is normally required.
• At the other end of the scale, stable patients on long-term
anticonvulsant or antidepressant therapy may need little or no
concentration monitoring in the absence of complications.
• Regular monitoring is useful (i) when optimizing dosage initially, (ii)
when other drugs are added to or subtracted from a regime, to guard
against known or unexpected interactions, or (iii) when renal or
hepatic function is changing.
• Drug distribution and the location (tissue and cell) of the drug’s target
influence the relationship between plasma drug concentration and effect.
• A constant tissue to plasma drug concentration ratio only occurs during the
terminal β-phase of elimination. Earlier in the dose interval, the plasma
concentration does not reflect the concentration in the extracellular tissue
space accurately.
• Measurements must be made when enough time has elapsed after a dose
for distribution to have occurred. Greater care is therefore required in the
timing and labelling of specimens for drug concentration determination than
is the case for ‘routine’ chemical pathology specimens.
• Usually during repeated dosing a sample is taken just before the next dose
to assess the ‘trough’ concentration, and a sample may also be taken at
some specified time after dosing (depending on the drug) to determine the
‘peak’ concentration.
 Lithium
• plasma concentrations are measured 12 hours
after dosing.