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THERAPEUTIC DRUG MONITORING (TDM)

1. Introduction:

(a) Because individual differences in pharmacokinetics are often enormous, there is a need to individualise the dosage of most drugs.

(b) “Average” of “usual” dosages can only apply when the therapeutic index of the drug is so large that, given pharmacokinetic variability, one dosage can be effective in all patients and excessive in none.

(c) Knowledge of plasma concentrations allows the individualisation of dosage with many drugs.

 

2. When TDM is Most Useful : Which Drugs to Monitor:

TDM is particularly useful for drugs belonging to the following categories:-

(a) Where the drug has a narrow therapeutic index (eg. Digoxin, Aminoglycosides, Theophylline, Anticonvulsants).

(b) Where the pharmacological effect is difficult to quantitate (eg. Salicylates, Lithium).

(c) Where drugs are used as prophylactic agents (eg. Anticonvulsants, Antiarrhythmics).

(d) Where there is an unpredictable relationship between drug dosage and plasma concentration (eg. Phenytoin, Salicylate).

3. When TDM is Not Useful:

(a) Unnecessary when dosage need not be individualised (eg. Penicillin V).

(b) Unnecessary when intensity of pharmacological effects can be clinically quantitated (eg. Hypoglycaemics, Anticoagulants, Antihypertensives).

(c) Useless when plasma concentration is not predictably related to intensity of pharmacological effects (eg. Anticoagulants).

(d) Not yet useful because concentration - effect relationship remains undefined (eg. Antidepressants).

At present, TDM is most useful for:-

(a) Cardiac glycosides (Digoxin).

(b) Antiarrhythmics (Lignocaine, Procainamide).

(c) Anticonvulsants (Phenytoin, Carbamazepine, Barbiturates).

(d) Lithium.

(e) Theophylline.

(f) Aminoglycoside antibiotics (Gentamicin, Fobramycin).

(g) Salicylate.

 

Table: Therapeutic concentration ranges and elimination half-lives of commonly monitored drugs

Drug	Therapeutic range·	Elimination half-life†
Amikacin	26 - 43 mol/L	1 - 7 h in adults; 0.7 - 3.0 h in children
Carbamazepine	21 - 51 mol/L	10 - 26 h in adults } long term 2 - 15h in children} therapy
Clonazepam	40 - 200 nmol/L	22 - 33 h
Digoxin	1 - 2.6 nmol/L	33 - 51 h
Disopyramide	9 - 18 mol/L	6 - 10 h
Ethosuximide	280 - 708 mol/L	60 h in adults; 30 h in children
Gentamicin	4 - 9 g/mL	0.5 - 3 h
Lignocaine	6 - 21 mol/L	1 - 1.5 h
Lithium	0.8 - 1.4 mol/L	7 - 20 h
Mexiletine	4.2 - 11.2 mol/L	9 - 12 h
Phenobarbitone	65 - 130 mol/L	1.5 - 3 days
Phenytoin	40 - 80 mol/L	About 24 h, within therapeutic range‡
Primidone§	23 - 46 mol/L	3 - 12 h
Procainamide	17 - 42 mol/L	2.5 - 4.5 h
Quinidine	3 - 9 mol/L	4 - 7 h
Salicylic acid	1086 - 2172 mol/L	2 - 20 h‡
Theophylline	28 - 111 mol/L	3 - 9 h
Tobramycin	4 - 9 g/mL	0.5 - 3 h
Valproic acid	350 - 700 mol/L	9 - 18 h in adults; 4 - 14 h in children
· These ranges often vary from laboratory to laboratory.  † These limits represent values for persons with normal renal, hepatic and cardiac function.  ‡ Because of capacity limited clearance, the “half-life” becomes longer with increasing dose and plasma concentration.  § Primidone metabolism results in the formation of Phenobarbitone, whose contribution must be considered when Primidone is administered

 

4. Particular Indications for Performing TDM : When to Monitor (Part I):

- To determine patient compliance.

- To evaluate apparent failure to respond.

- To confirm suspected toxicity.

- When clinical circumstances change rapidly (eg. alterations in circulatory, hepatic, or renal function).

- When drug interaction is likely.

- When systemic availability is likely to change (eg. new drug preparation, altered circulatory state, affecting absorption).

5. When to Monitor (Part II) : Time of Sampling:

(a) Achieve steady-state conditions.

(b) In general, the sampling time should be just prior to the next dose for conventional formulations.

(i) Large inter and intra-patient variation in peak level following absorption.

(ii) By time of trough level, can be assured that equilibration of drug between blood and target tissue will have occurred.

6. Common Errors in TDM:

- Failure to appreciate the practical limitations of the “therapeutic range” of plasma drug concentrations.

- Inappropriate sampling time in relation to dose.

- Incorrect assumption of “steady-state” conditions after a change in drug dose.

- Failure to understand the potential effect of the disease state on drug handling.

- Fixed belief in the superiority of biochemical over clinical data.

7. Example - Phenytoin:

(a) Historically prescribed in a total daily dosage of 300mg.

(b) With the advent of Phenytoin level monitoring, this dose was found to produce > 10-fold variation in plasma level.

(c) Individualised dosages now vary within a range of ~ 150 - 700mg/day.

Advantages of Phenytoin level monitoring:

(a) Large individual variation in pharmacokinetics.

(b) Pharmacological effect (Prophylaxis of fits) is not easily quantifiable clinically.

(c) Therapeutic (optimum) range of plasma levels well established, ie. 40 - 80 mmol/L.

(d) Non-linear (dose dependent) pharmacokinetics.

8. Conclusion:

TDM is a valuable procedure in therapeutics, since it minimises the effects of individual pharmacokinetic variability and so improves the chances of achieving optimal therapeutic results. However, appropriate use of TDM requires a sound knowledge of basic clinical pharmacology/pharmacokinetics and an appreciation of the fact that test results are no substitute for clinical judgement.