Measuring plasma concentration

The most frequently used assays measure the total plasma concentration of a drug. With drugs that are protein bound, changes in plasma protein concentration may have a disproportionate effect on the total drug concentration relative to the amount free in the plasma and thus available to tissues. The assay chosen must be specific for the drug itself (or its active metabolite where appropriate) and should not measure inactive metabolites or be affected by other drugs that the patient may be taking.

As with other biochemical measurements, plasma concentrations of drugs are compared with standard data. The term ‘reference range’ is inappropriate in this context, because healthy people will not be taking the drug. The term ‘therapeutic’ or ‘target’ range is used instead. This is the range between the minimum effective concentration of the drug and the maximum safe concentration. Often, only the upper limit is stated, as a drug may be efficacious in some individuals at concentrations below the generally accepted minimum effective concentration. On the other hand, optimum management may sometimes require that the concentration of a drug is maintained above the upper limit of the therapeutic/target range. Such ranges are not absolute: for example, hypokalaemia increases sensitivity to digoxin and effectively lowers the upper limit. The plasma concentrations of therapeutic drugs must always be considered in context with clinical information: decisions should not be based on concentrations alone, unless these are in an unequivocally toxic range.

Readers should be aware that the concentrations of drugs (and toxins) in body fluids may be reported in either mass units (e.g. mg/L) or molar units (e.g. mmol/L). In the UK, the consensus view is that mass units should be used, except for a few substances that have always been reported in molar units (including iron, lithium, methotrexate and thyroxine) or are so reported because the units are enshrined in legislation (e.g. lead).

When a drug is first taken, the plasma concentration rises relatively rapidly as it is absorbed, and then falls, more slowly, as it is taken up into tissues, metabolized and excreted. Many drugs are taken in doses and at intervals such that a steady-state plasma concentration is achieved. This occurs after a period equivalent to five half-lives, and is often the most relevant concentration to measure. For some drugs with short half-lives, significant fluctuations in plasma concentration occur and it is the peak or trough concentrations, achieved shortly after and immediately before the drug is taken, respectively, that are measured.

In the following section, the use of plasma measurements of a few representative and commonly used drugs is discussed to illustrate the general principles of therapeutic drug monitoring.

Phenytoin

The therapeutic effectiveness of this frequently prescribed anticonvulsant drug is difficult to assess without monitoring. It has a low therapeutic ratio and the signs of toxicity may mimic the neurological diseases that can be associated with epilepsy. Furthermore, phenytoin has unusual pharmacokinetic properties: the enzyme responsible for the elimination of the drug (hepatic CYP2C9) becomes saturated within the therapeutic range of plasma concentrations, giving rise to zero-order kinetics. This phenomenon has several important implications. In particular, the relationship between plasma concentration and dose is non-linear (Fig. 19.3); thus small increments in dose may lead to disproportionate increases in steady-state plasma concentrations. On the other hand, even if the dose is unchanged, a small decrease in drug-metabolizing enzyme activity, or the presence of other drugs that inhibit phenytoin metabolism, could transform a therapeutic plasma concentration to a toxic concentration. Figure 19.3 also indicates the wide variation of doses required to achieve therapeutic plasma concentrations in different individuals.

Figure 19.3 Relationship between the steady-state serum concentration of phenytoin and dose; 20 mg/L is the upper limit of the therapeutic range. Data for five patients are shown.

(Adapted from Richens A. and Dunlop A. (1975) Serum phenytoin levels in the management of epilepsy. Lancet 2: 247–248.)

The measurement of plasma phenytoin concentration is also useful if adverse effects occur, if there is an unexplained deterioration in the patient’s control, during intravenous therapy in status epilepticus and if a drug known to interact with phenytoin has to be prescribed. It is of particular value in children and during pregnancy, when dramatic fluctuations in plasma concentrations and in epileptic control may occur. As emphasized above, however, measurements should be interpreted in the light of clinical circumstances: some patients only achieve effective control of seizures at plasma concentrations greater than the upper limit of the target range, yet do not experience toxicity, while others, particularly older patients, may achieve good control at relatively low concentrations.

Other anticonvulsants

The value of measuring the plasma concentrations of some other anticonvulsant drugs is shown in Figure 19.4. Carbamazepine induces its own metabolism and interactions occur with other anticonvulsants. Monitoring (of trough concentrations) is valuable when carbamazepine is first prescribed, if seizure control is difficult to achieve and if other anticonvulsants are being used, but is complicated by the fact that the drug has active metabolites, which are not measured in the standard assay. The dosage of ethosuximide can often be adjusted on clinical grounds, as toxicity is easily recognizable when the drug is being used alone. The plasma concentration of lamotrigine reflects its effect and TDM is usually recommended, particularly when the drug is used with phenytoin or carbamazepine (which reduce its plasma half-life) or valproate (which prolongs it). With sodium valproate there is no clear safe maximum concentration, there is a poor correlation between plasma concentration and efficacy, and hepatotoxicity, which is anyway rare, cannot be predicted from plasma concentration. There is a poor correlation between plasma concentrations of phenobarbital and either clinical or toxic effects, so that routine monitoring is of little value (an exception is with its use in children as prophylaxis for febrile convulsions). TDM of vigabatrin is unnecessary. Plasma concentrations show little relationship with clinical effect, probably because the drug binds irreversibly to its target enzyme (γ-aminobutyric acid transferase) in the brain. TDM for clonazepam, gabapentin, levetiracetam and oxcarbazepine is not required; neither is it for felbamate, although the toxicity of this drug requires that liver function and full blood count are monitored regularly.

Figure 19.4 Therapeutic monitoring of anticonvulsant drugs. For other anticonvulsants, see text.

Digoxin

Digoxin is frequently used in the management of cardiac failure with atrial fibrillation, a common problem in the elderly. Plasma digoxin measurements are valuable not only in the assessment of the appropriate dose to prescribe, but also in the diagnosis of digoxin toxicity and in assessing patient compliance. Failure to take a prescribed medication (non-compliance) is a common cause of failure to achieve a therapeutic response.

The therapeutic range for plasma digoxin concentration in heart failure is generally taken as 0.5–1.0 µg/L. There is a significant increase in plasma concentration following a dose of the drug and a minimum period of 6 h should elapse before blood is drawn for assessment of the mean steady-state concentration. In practice, it is often simplest, and satisfactory for clinical purposes, if a blood sample is taken shortly before a dose is due.

While the therapeutic effect is minimal when the plasma concentration is below 0.5 µg/L and toxicity becomes more common at concentrations above 1.0 µg/L and is almost invariable if they exceed 3.0 µg/L, there is in general a rather poor correlation between plasma concentration of digoxin and therapeutic effect.

This phenomenon is partly a result of the existence of various factors that alter either the therapeutic response to a given plasma concentration of digoxin or the plasma concentration achieved on a particular dose (Fig. 19.5). Hypokalaemia is a particular problem because many patients treated with digoxin are also receiving diuretics, which may cause this (see Case history 21.2). In addition, renal impairment may be a consequence of congestive cardiac failure; this is important because digoxin is mostly eliminated via the kidneys. It is thus very important to consider the clinical setting when assessing the significance of plasma digoxin concentrations. It is good practice always to measure the plasma potassium concentration when digoxin is measured.

Figure 19.5 Factors affecting sensitivity to digoxin. In addition, renal impairment and hypothyroidism may increase the plasma concentration of digoxin in relation to the dose taken; hyperthyroidism may decrease the concentration.

Digoxin concentrations are also useful in the diagnosis of digoxin toxicity. This is important because some of the features of toxicity are relatively non-specific (e.g. nausea and vomiting), while others include dysrhythmias that could possibly be a complication of the underlying heart disease. It is important that the possible influence of pathological and physiological factors is considered (see Fig. 19.5).

If a patient taking digoxin is symptom-free yet has a plasma concentration less than 0.5 µg/L, it is likely that the drug is not required, and it may be withdrawn, although under supervision.

The occurrence of endogenous substances that bind to the antibodies used in digoxin immunoassays (digoxin-like immunoreactive substances, DLIS) can (albeit occasionally) cause spurious apparent elevations in digoxin concentrations. Such interference should be suspected if unexpectedly high concentrations are found and the measurement repeated using a different method (because the extent to which antibodies supplied by different manufacturers react with DLIS varies).