For the theophylline example given in the box, Example: Maintenance Dose Calculations, the loading dose would be 350 mg (35 L × 10 mg/L) for a 70-kg person. For most drugs, the loading dose can be given as a single dose by the chosen route of administration.
Up to this point, we have ignored the fact that some drugs follow more complex multicompartment pharmacokinetics, eg, the distribution process illustrated by the two-compartment model in Figure 3–2. This is justified in the great majority of cases. However, in some cases the distribution phase may not be ignored, particularly in connection with the calculation of loading doses. If the rate of absorption is rapid relative to distribution (this is always true for rapid intravenous administration), the concentration of drug in plasma that results from an appropriate loading dose—calculated using the apparent volume of distribution—can initially be considerably higher than desired. Severe toxicity may occur, albeit transiently. This may be particularly important, eg, in the administration of antiarrhythmic drugs such as lidocaine, where an almost immediate toxic response may occur. Thus, while the estimation of the amount of a loading dose may be quite correct, the rate of administration can sometimes be crucial in preventing excessive drug concentrations, and slow administration of an intravenous drug (over minutes rather than seconds) is almost always prudent practice.
When intermittent doses are given, the loading dose calculated from equation (12) will only reach the average steady-state concentration and will not match the peak steady-state concentration (Figure 3–6). To match the peak steady-state concentration, the loading dose can be calculated from equation (13):
TARGET CONCENTRATION INTERVENTION: APPLICATION OF PHARMACOKINETICS & PHARMACODYNAMICS TO DOSE INDIVIDUALIZATION
The basic principles outlined above can be applied to the interpretation of clinical drug concentration measurements on the basis of three major pharmacokinetic variables: absorption, clearance, and volume of distribution (and the derived variable, half-life). In addition, it may be necessary to consider two pharmacodynamic variables: maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug. Diseases may modify all of these parameters, and the ability to predict the effect of disease states on pharmacokinetic parameters is important in properly adjusting dosage in such cases. (See Box: The Target Concentration Strategy.)
A. Input
The amount of drug that enters the body depends on the patient’s adherence to the prescribed regimen and on the rate and extent of transfer from the site of administration to the blood.
C. Volume of Distribution
The apparent volume of distribution reflects a balance between
Recognition of the essential role of concentration in linking pharmacokinetics and pharmacodynamics leads naturally to the target concentration strategy. Pharmacodynamic principles can be used to predict the concentration required to achieve a particular degree of therapeutic effect. This target concentration can then be achieved by using pharmacokinetic principles to arrive at a suitable dosing regimen (Holford, 1999). The target concentration strategy is a process for optimizing the dose in an individual on the basis of a measured surrogate response such as drug concentration: 1.
Choose the target concentration, TC.
2.
Predict volume of distribution (V) and clearance (CL) based on standard population values (eg, Table 3–1) with adjustments for factors such as weight and renal function.
3.
Give a loading dose or maintenance dose calculated from TC, V, and CL.
4.
Measure the patient’s response and drug concentration.
5.
Revise V and/or CL based on the measured concentration.
6.
Repeat steps 3–5, adjusting the predicted dose to achieve TC.