Two horizontal lines can be placed over the Cp/time curve, indicating therapeutic threshold and ceiling. The space between these two lines is called the therapeutic window (Figure 13). Drug treatment aims at plasma concentrations within this therapeutic window. The possible variables to be considered are therefore (1) the position and the width of the window, and (2) the profile of the curve.

Figure 13: Cp/time curve and therapeutic window

Therapeutic window

The position and the width of the window are determined by pharmacodynamic factors (Figure 14). The position of the window may shift upwards in case of resistance by the patient or competitive antagonism by another drug: a higher plasma concentration is needed to exert the same effect. The window can shift downwards in case of hypersensitization or synergism by another drug: a lower plasma concentration is needed.

Figure 14: Place and width of therapeutic window

The width of the window may also vary. It may become narrower in case of a decreased safety-margin. For example, the therapeutic window of theophylline is narrower in small children than in adults. A broader window usually has no consequences.

Curve

The profile of the curve is determined by four factors: Absorption, Distribution, Metabolism and Excretion. These are usually referred to as ADME factors. Although most treatments consist of more than one dose of a drug, some pharmacokinetic parameters can best be explained by looking at the effect of one dose only.

One of the most important parameters is the half-life of a drug (Figure 15). Most drugs are eliminated by means of a first-order process. This means that per unit of time the same percentage of drug is eliminated, for example 6% per hour. The half-life of a drug is the time it takes to decrease the plasma concentration to half of its initial value. With 6% per hour the half-life is about 11 hours (if no more of the drug is given in the meantime). After 2 half-lives (22 hours) it will be 25%; after 3 half-lives 12.5%; and after 4 half-lives 6.25%. If the original plasma concentration falls within the therapeutic window, a decline to 6.25% will usually be far below the therapeutic threshold. For this reason it is usually said that drugs no longer have a pharmacological effect 4 half-lives after the last dose.

Figure 15: Half-life of a drug