The TDM Guidelines

Copyright ^© [Regional Laboratory for Toxicology], 2002. All rights reserved.

INTRODUCTION

Therapeutic drug monitoring (TDM) is only of value for a limited number of drugs. For such measurements to be clinically worthwhile, the following criteria should be fulfilled:-

1. Established relationship between plasma drug concentration and therapeutic response and/or toxicity;

2. Poor relationship between plasma concentration and drug dosage;

3. A good clinical indication for the test such as : no response to treatment; suspected non-compliance; signs of toxicity;

4. The collection of an appropriately timed and dated specimen with proper patient information;

5. Adequate clinical information to allow the interpretation of results.

 

THE SERVICE OFFERED

The Laboratory currently offers a routine service for the measurement of the following drugs in plasma:-

Emergency within-hours services are available for TDM provided that there is sufficient clinical justification for the request. In such a case, the Laboratory must be consulted prior to the despatch of the specimen (see Contact Points). The Laboratory can usually provide a result within 30 minutes of receipt of the specimen. Highlighted assays may be available out-of-hours following discussion with the laboratory or the Poisons Unit on ward D8 (see Contact Points).

Twice Daily Service Monday - Friday

Anticonvulsant drugs: Carbamazepine, Ethosuximide, Phenytoin, Phenobarbitone, Valproic acid.

Cardioactive drug: Digoxin

Respiratory stimulants: Caffeine, Theophylline.

Twice Weekly Service

Gabapentin, Lamotrigine, , Vigabatrin.

Weekly Service

Tricyclic antidepressants: Amitriptyline, Clomipramine, Desipramine, Dothiepin, Imipramine, Nortriptyline.

SSRI antidepressants: Fluoxetine (prozac).

It is important to record the exact time and date of the specimen in relation to the last dose of the drug, with a note of all other drugs prescribed.

TDM SERVICE FOR OTHER DRUGS

The Laboratory is able to provide information and guidance concerning measurement of those drugs not listed above.

SPECIMEN COLLECTION

In general, a blood specimen should not be taken until "steady-state" has been achieved (approximately five times the drug's half-life). This applies to changes in dosage as well as following the initiation of therapy. Please refer to Table 1 for further guidance on sampling times and minimum sample volumes required for the analysis of specific drugs. For a complete listing of sample volumes and the types of container for each specimen, please refer to the table listing all assay sample requirements.

QUALITY ASSURANCE

The TDM services of the Laboratory are monitored both by internal controls, assayed every time a batch of samples is processed, and by external controls, assayed monthly. The Laboratory participates in and has a high ranking in both the HeathControl scheme (Cardiff) and the United Kingdom National External Quality Assessment Service (NEQAS).

TARGET OR THERAPEUTIC RANGE

Note that the "target" or "therapeutic" range is only a guide to proper dosing of the patient. Aim to treat the whole patient rather than the drug concentration. Table 1 indicates the therapeutic ranges that the Laboratory currently applies to TDM results.

NOTES ON INDIVIDUAL DRUGS

Amitriptyline - Steady-state plasma concentrations generally obtained within 7 - 10 days of starting treatment, although maximum clinical benefit may take up to 4 - 6 weeks to be achieved. The main active metabolite, nortriptyline is also measured. Blood specimens should be taken just prior to dosing (trough concentration).Target range 100 - 250 µg/L.

Caffeine - When used to treat apnoeic attacks in neonates, plasma caffeine concentrations appear to correlate with clinical effects. In addition to plasma concentrations, clinical symptoms of toxicity (irritability and tachycardia) should be monitored during treatment. Target range 12 - 36 mg/L.

Carbamazepine - Induces its own metabolism so that following the initiation of therapy, it takes 2 - 4 weeks to obtain a steady state. Treatment should, therefore, commence with low doses, increasing at weekly intervals for the first month. Target range 4 - 12 mg/L. There is no clinical value in quantifying the epoxide or other metabolites of carbamazepine.

Clomipramine - Steady-state plasma drug concentrations may take up to 4 - 6 weeks to be achieved. Blood specimens should be taken just prior to dosing (trough concentration).

Desipramine - Steady-state plasma concentrations are generally obtained within 7-10 days of starting treatment, although maximum clinical benefit may take up to 4-6 weeks to be achieved. Blood specimens should be taken just prior to dosing (trough concentration).

Digoxin - The low therapeutic index of digoxin means that dose adjustment must be performed with caution. Results can only be interpreted correctly if samples are taken at least 6 h post-dose to ensure that distribution of digoxin is complete. Digoxin elimination is strongly influenced by renal function. Hypokalemia and hypomagnesia may influence (increase) myocardial sensitivity to digoxin.

Dothiepin - Steady-state plasma concentrations are generally obtained within 7 - 10 days of starting treatment, although maximum clinical benefit may take up to 4-6 weeks to be achieved. The active metabolite, nordothiepin, is also measured. Blood specimens should be taken just prior to dosing (trough concentration).

Ethosuximide - There is good correlation between dose and plasma concentration, and a high therapeutic index for this drug. Steady-state in children is achieved in 5 - 7 days, compared with 10 - 14 days in adults.

Fluoxetine – This is the most widely prescribed of the SSRI group of antidepressants. Steady-state plasma drug concentrations may take between 4 - 6 weeks to be achieved. The main active metabolite, norfluoxetine, is also measured. This drug is also a potent inhibitor of drug metabolising enzymes and may cause an increase in plasma drug concentrations of other drugs if prescribed at the same time. Blood specimens should be taken just prior to dosing (trough concentrations).

Gabapentin - Absorption of gabapentin is very rapid with peak concentrations occurring at 2-3 hours. The elimination half-life of 5-7 hours necessitates dosing three times daily, but steady state is achieved within 1-2 days. The drug is eliminated entirely via the kidneys as unchanged compound, resulting in the clearance being proportional to renal function.

Imipramine – Steady-state plasma drug concentrations are generally obtained within 7-10 days of starting treatment, although maximum clinical benefit may take up to 4-6 weeks to be achieved. The main active metabolite, desipramine, is also measured. Blood specimens should be taken just prior to dosing (trough concentration).

Lamotrigine - Concomitant therapy with other anticonvulsants has a marked effect on clearance. Valproate doubles the half-life from 25 to 48 hrs, whilst carbamazepine and phenobarbitone reduce the half-life to around 12 hrs. There is some evidence that adverse effects of lamotrigine may be concentration dependent.

Nortriptyline - Steady-state plasma concentrations generally obtained within 7 - 10 days of starting treatment, although maximum clinical benefit may take up to 4 - 6 weeks to be achieved. Blood specimens should be taken just prior to dosing (trough concentration).

Phenobarbitone - Results on samples taken before steady-state has been achieved (1 - 2 weeks in children; 2 - 4 weeks in adults) will be unhelpful, except to confirm a diagnosis of toxicity.

Phenytoin - Monitoring is imperative as a guide to dosage adjustment, since phenytoin has a low therapeutic index and exhibits saturation kinetics (i.e. small increases in dose result in large increases in concentration).

Theophylline - Plasma concentrations are related predictably to both bronchodilator and toxic effects. Theophylline can be metabolised to caffeine in neonates, and in some adults where there is impairment of hepatic drug metabolism.

Valproic acid - The anticonvulsant activity and toxicity of valproic acid show no simple relationships to its plasma concentration. Hence there is generally little clinical value in the measurement of valproic acid. The short plasma half-life results in large variations in plasma concentrations between doses.

Vigabatrin - Vigabatrin irreversibly inhibits the enzyme GABA-Transaminase thereby increasing the concentration of GABA in the brain and decreasing the propagation of abnormal discharges.

REQUEST FORMS

The Department no longer requires specific request forms for TDM to be used. Outside laboratories may use their own local request forms since all data is transferred to computer generated reports along with analytical results. It is, however, essential that all patient details and analytical requests are completed legibly, and that the date and time of sampling and the time post drug administration is documented.

CHARGES

For those investigations not covered by any existing contractual arrangement, the charges for individual investigations are shown in the current price list available from the laboratory on request.

Invoices are sent on a monthly basis and are payable within 30 days of issue.

CONTACT POINTS:

Dr. S.A. George, Senior Biochemist and Section Head: 'phone (0121) 507 6029

Dr. R.A. Braithwaite, Head of Department: 'phone (0121) 507 4134

FAX No: (0121) 507 6021

West Midlands Poisons Unit on Ward D8: 'phone (0121) 507 4007, 4307

TABLE 1. SAMPLING TIMES AND TARGET RANGES FOR TDM ASSAYS

KEY:

pre-dose* Collection time unimportant , due to the long half-life of the drug; however, for consistency, a pre-dose measurement is preferred.

(1) Theophylline used to treat asthma in adults.

(2) Theophylline used to treat neonatal apnoea.

(3) For valproic acid there is no established target range. If the pre-dose concentration is greater than 100 mg/L with no clear therapeutic effect, then further increases in dose are unlikely to be beneficial.

It should be noted that "Target" ranges are given as guidance and should not be used as rigid limits.

Last modified: April 13, 2005

Copyright ^© [Regional Laboratory for Toxicology], 2002. All rights reserved.

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