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Analytical requirements Timing of measurements

المؤلف:  Sue Jickells , Adam Negrusz (Editors)

المصدر:  Clarkes Analytical Forensic Toxicology

الجزء والصفحة:  251-252

2026-10-19

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Analytical requirements

Timing of measurements

The primary requirement for an appropriate specimen if TDM is to be used to assess the adequacy of response is that the specimen be taken when the drug concentration in the body is at a steady state and the effects of any recent dose changes have been allowed to stabilise. The time to reach steady state is determined by the elimination half-life of the drug, and there is a fixed relationship between the number of half-lives that have elapsed since the drug was commenced and the progress towards steady state concentration (see Chapter 2). The plasma concentration after 3.3 half-lives have elapsed is 90% of the predicted steady-state concentration, and 94% of steady-state concentration is reached after four half-lives. For drugs with a long plasma half-life (for example, digoxin and phenytoin), a week or two (or even longer) may be required before steady state is obtained, especially if renal function is poor in the case of digoxin. It is usual to allow at least four elimination half-lives to elapse before monitoring the effect of any dose change, although obviously if toxicity is suspected after a dose change it would be unwise to wait for steady state before checking the plasma concentration. As it takes four half-lives to be at steady state, it takes the same time to eliminate the drug out of the plasma. Amiodarone has an extreme half-life and this can be the reason the clinician cannot wait for the making of an ECG. The amiodarone serum level may be useful for interpretation of its influence on the ECG. Computer programs with the ability to predict steady-state concentrations from measurements made before steady state is attained may also be helpful.

The other issue that relates to the appropriate sample timing is the question of when the sample should be taken in relation to the last dose of the drug. As drugs are normally administered at fixed time intervals, inevitably there is a variation of plasma concentration between one dose and the next. For most purposes, the most reproducible parameter for long-term monitoring is the steady-state trough concentration a measurement immediately prior to the next oral dose. The importance of precise sample timing depends somewhat on the half-life of the drug – drugs with long half-lives (e.g. phenytoin) show little variation in concentration across the dosage interval, and accurate specimen timing is less important than for short-half-life drugs like theophylline and lithium. For these drugs, toxic symptoms may correlate better with peak plasma concentrations than trough concentrations, and if toxicity is suspected a sample timed at 1–6 h post dose (depending on the release characteristics of the preparation and the speed of absorption) may be more appropriate. Some antibiotics require high peak concentrations and low trough concentrations for optimal effects (e.g. amino glycosides), while others require the maintenance of high trough concentrations (e.g. vancomycin). In the case of lithium, a strong case has been made to standardise the sampling time at exactly 12 h post dose. The area under the concentration–time curve (AUC), or the concentration at an intermediate time point, may also be a better predictor of response than either the peak or the trough concentration (e.g. in the case of ciclosporin, where the 2-hour post dose concentration is now sometimes used). The determination of AUC requires more complex sampling regimes. Some drugs exhibit a distribution phase immediately after the dose has been given, and for the duration of this phase the plasma concentration is unrepresentative of the pharmacologically relevant receptor concentration. This is particularly the case for digoxin, for which clinically misleading concentrations may be obtained in the first 4 or 5 h following a dose (whether oral or intravenous) while the drug equilibrates between plasma and tissue compartments.