Earlier chapters of this book discussed single-dose drug administration. Generally, drugs are given in multiple doses to treat chronic disease such as arthritis, hypertension, etc. After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect. To treat chronic disease, multiple-dosage or IV infusion regimens are used to maintain the plasma drug levels within the narrow limits of the therapeutic window (eg, plasma drug concentrations above the MEC but below the minimum toxic concentration or MTC) to achieve optimal clinical effectiveness. These drugs may include antibacterials, cardiotonics, anticonvulsants, hypoglycemics, antihypertensives, hormones, and others. Ideally, a dosage regimen is established for each drug to provide the correct plasma level without excessive fluctuation and drug accumulation outside the therapeutic window.
For certain drugs, such as antibiotics, a desirable MEC can be determined. Some drugs that have a narrow therapeutic range (eg, digoxin and phenytoin) require definition of the therapeutic minimum and maximum nontoxic plasma concentrations (MEC and MTC, respectively). In calculating a multiple-dose regimen, the desired or target plasma drug concentration must be related to a therapeutic response, and the multiple-dose regimen must be designed to produce plasma concentrations within the therapeutic window.
There are two main parameters that can be adjusted in developing a dosage regimen: (1) the size of the drug dose and (2) τ, the frequency of drug administration (ie, the time interval between doses).
To calculate a multiple-dose regimen for a patient or patients, pharmacokinetic parameters are first obtained from the plasma level–time curve generated by single-dose drug studies. With these pharmacokinetic parameters and knowledge of the size of the dose and dosage interval (τ), the complete plasma level–time curve or the plasma level may be predicted at any time after the beginning of the dosage regimen.
For calculation of multiple-dose regimens, it is necessary to decide whether successive doses of drug will have any effect on the previous dose. The principle of superposition assumes that early doses of drug do not affect the pharmacokinetics of subsequent doses. Therefore, the blood levels after the second, third, or nth dose will overlay or superimpose the blood level attained after the (n – 1)th dose. In addition, the AUC = for the first dose is equal to the steady-state area between doses, ie, as shown in Fig. 8-1.
Simulated data showing blood levels after administration of multiple doses and accumulation of blood levels when equal doses are given at equal time intervals.
The principle of superposition allows the pharmacokineticist to project the plasma drug concentration–time curve of a drug after multiple consecutive doses based on the plasma drug concentration–time curve obtained after a single dose. The basic assumptions are: (1) that the drug is eliminated by first-order kinetics ...