Therapeutic drug monitoring (TDM) pitfalls and limitations

doi:10.15406/mojt.2014.01.00002

MOJ

eISSN: 2379-6294

Toxicology

Editorial Volume 1 Issue 1

Therapeutic drug monitoring (TDM) pitfalls and limitations

Mohamed Enara

Verify Captcha

Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers. Please type the correct Captcha word to see email ID.

Poison Control University, Canada

Correspondence: Mohamed Enara, Poison Control University, Toronto, Ontario, Canada, Tel 4162 250853

Received: August 11, 2014 | Published: November 26, 2014

Citation: Enara M. Therapeutic drug monitoring (TDM) pitfalls and limitations. MOJ Toxicol. 2014;9(10):9–10. DOI: 10.15406/mojt.2014.01.00002

Download PDF

Aim

TDM is a very important and widely used technique throughout the treatment process. Analysis is done for a range of drugs in blood for the following reasons:

To establish baseline values during therapy.
When a patient is refractory to therapy.
Non-compliance suspected.
When toxicity is suspected (similar symptoms of toxicity and under treatment) e.g. arrhythmia in digoxin, seizures in phenytoin…
Modifying dosage or concomitant therapy.
To achieve maximum therapeutic benefit and decrease unwanted effects.

We use the fact that when there is a sufficient relationship between the plasma level of the drug and its clinical effect, it is then useful to measure this level. If such a relationship does not exit, TDM is of little or no value. Based on this fact, the TDM will be of maximal benefit when:

Low therapeutic index of a drug.
The drug metabolites in plasma have a relation to its pharmacological or toxic effects.
We cannot determine the therapeutic effect relying on the clinical observation.
There is an individual variation which is great in steady state.
Plasma concentration exists at any given dose.
Appropriate analytical techniques are readily and easily present.

Subsequently, the TDM is not done for:

Drugs with large therapeutic index e.g. cephalosporin’s.
Drugs with serum concentration not related to the clinical response.
When we can measure the clinical response directly e.g. blood pressure, blood glucose.

So now the concept is clear. What are the drugs that are suitable candidates for TDM technique?

Digoxin
Quinidine
Carbamazepine
Phenobarbitone
Phenytoin
Valproic acid
Gentamycin
Vancomycin
Cyclosporine
Theophylline
Tricyclic antidepressants
Acetyl salicylic acid.

But sometimes we face problems. What to look for when you get an unexpected serum concentration?

Is there a non-compliance
Is the dose correct
Does the patient suffer from mal-absorption
Does the drug has a low bioavailability
Look for concomitant drugs that could affect the dose of the drug in question
Make sure of good hepatic or renal conditions
Diseases related to genetic factors affecting drug metabolism.

If you face these abnormalities, what is the solution for these problems? We can start with a dosage adjustment. We can use the following formula for linear drugs.

$N e w d o s e = O l d d o s e \times \frac{d e s i r e d c o n c e n t r a t i o n}{o l d c o n c e n t r a t i o n}$

We then must be aware of the factors leading to pitfalls. These could be summarized as:

Timing of Sample collection
Dosage regimen
Infusion length
Disease state
Effect of age
Pregnancy
Others

Let us discuss some of these in more details.

Discussion

Timing of sample collection

The importance of proper timing of a sample is not given sufficient attention while ordering measurement of a plasma concentration. Ideal timing should be 4 to 5 half-lives (time to reach steady-state).

Dosage regimen

We have to revise thoroughly the regimen of the treatment given, regarding the dose and frequency, specially the last dose before the test.

Infusion length

Please refer to the following (Table 1) for determination of the peak serum level.

Infusion	Dose	Interval	Peak level
30min	500mg	8hrs	26.8
60min	500mg	8hrs	25.3
120min	500mg	8hrs	22.5

Table 1 Determination of the peak serum level

Effect of disease states

Revision of the pharmacokinetics of the drug in question is important to know the effect of acute or chronic disease states on its clearance patterns.

Effect of age

There is a great variability in response to drugs at extremes of age. As an example, elderly patients are more sensitive to the CNS depressant effect of drugs but are less sensitive to cardiovascular effects of Propranolol. It is well known that children are more sensitive to morphine.

Pregnancy

Many drugs can be affected by pregnancy state. As an example, drug levels of phenytoin and phenobarbitone are lower during pregnancy.

Other TDM precautions

This is a rule of thumb! We have to rule out errors before accepting out-of-range data .

What are the most common pitfalls and error sources?

Time of administration of the drug is not accurate .
Dose administration error.
Inaccurate time of sampling, or timing was before steady-state is reached
Wrong site of sampling.
Lab assay error .
Pharmacy dispensing error

Conclusion

Lastly, the TDM is a very useful method for achieving a highest benefit of a drug and avoiding most of its side effects if done properly. Avoiding its pitfalls will gain us the maximum benefit of the procedure.