Principles of Therapeutic Drug Monitoring

Physicians use pharmaceuticals to treat a vast variety of clinical conditions. Plasma drug concentrations within the therapeutic range have a high probability of achieving the desired clinical response and a low probability of manifesting toxic side effects. Conversely, drug levels below the minimum effective concentration (MEC) are unlikely to have the desired effects, and levels greater than the minimum toxic concentration (MTC) become increasingly toxic.

The variables (pharmacokinetic parameters) determining optimum dosage regimens include the target plasma concentration (usually the midpoint of the therapeutic range), the rate at which the drug is cleared from the circulation by hepatic metabolism and/or renal function, the (bioavailable) fraction of the administered dose absorbed into the circulation, the unbound (bioactive) fraction in the plasma, and a parameter referred to as "volume of distribution" that reflects the degree to which the drug is distributed from plasma into tissue compartments of the body.

Patients must be individually monitored to ensure that drug concentrations are optimal throughout the course of the treatment. Factors that may require patient-specific adjustments include genetic variation; normal alterations in physiology (sex, age, and pregnancy); and pathophysiological changes as a consequence of disease, surgery and, over time, the drug treatment regimen itself.

In long-term therapy, orally administered drugs accumulate in the body until the rate of elimination is equal to the rate of administration. The time required to reach this steady-state plateau is expressed in terms of the drug half-life: the time required for the plasma drug concentration to decline by one half. Steady state is essentially complete after five to seven half-lives (Figure 1).

Figure 1.

The drug concentration exhibits a characteristic rise and fall as a function of time after each dose is administered. Both the peak and trough levels rise until steady state is achieved after approximately five to seven half-lives. At steady state, the trough levels (Cmin_ss) remain below the minimum toxic concentration (MTC), i.e., within the therapeutic range. In this example, the dosing interval (t) is equal to the elimination half-life (T).

Dosing cycles may be once each half-life. To avoid excessive fluctuations of drug concentrations at steady state, however, smaller dosages may be given more frequently. Routine therapeutic drug monitoring (TDM) usually involves sampling at the time of the next administered dose to obtain trough (minimum) concentrations. However, if drug toxicity is of concern, sampling may be performed at an appropriate time after the dose to obtain peak drug concentrations.

TDM is the discipline that provides the tools required to identify optimal therapeutic regimens, to ensure patient compliance with the prescribed dosing cycle, to ensure that drug concentrations are maintained within the therapeutic range throughout the entire course of drug therapy, and to recognize and anticipate significant changes in pharmacokinetic parameters during the course of the drug treatment regimen. In this regard, TDM results reported by the laboratory are extremely useful, though they must, of course, be interpreted in conjunction with the patient's overall clinical presentation. Such monitoring is essential for drugs that have relatively narrow therapeutic ranges and profoundly toxic side effects.

Assays for seven frequently used therapeutic drugs will soon be available on DPC's IMMULITE® platform. DPC currently offers IMMULITE assays for the cardiotonic drugs digoxin and digitoxin, as well as an assay for the bronchodilator theophylline. Assays for the antiepileptic drugs carbamazepine, phenobarbital, phenytoin and valproic acid will follow shortly.

DPC will soon publish a technical report on therapeutic drug monitoring that will contain clinical, analytical, and monitoring-related information for each of these drugs. The electronic version will appear on DPC's web site—www.dpcweb.com.