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A dosage regimen is a plan for drug administration over a period of time. An optimal dosage regimen results in the achievement of therapeutic levels of the drug in the blood without exceeding the minimum toxic concentration. To maintain the plasma concentration within a specified range over long periods of therapy, a schedule of maintenance doses is used. If it is necessary to achieve the target plasma level rapidly, a loading dose may be used to “load” the Vd with the drug. Ideally, the dosing plan is based on knowledge of both the minimum therapeutic and minimum toxic concentrations for the drug, as well as its clearance and Vd.
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A. Maintenance Dosage
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Because the maintenance rate of drug administration is equal to the rate of elimination at steady state (this is the definition of steady state), the maintenance dosage is a function of clearance (from Equation 2).
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Note that Vd is not involved in the calculation of maintenance dosing rate. The dosing rate computed for maintenance dosage is the average dose per unit time. When performing such calculations, make certain that the units are in agreement throughout. For example, if clearance is given in mL/min, the resulting dosing rate is a per minute rate. Because convenience of administration is desirable for chronic therapy, doses should be given orally if possible and only once or a few times per day. The size of the daily dose (dose per minute × 60 min/h × 24 h/d) is a simple extension of the preceding information. The number of doses to be given per day is usually determined by the half-life of the drug and the difference between the minimum therapeutic and toxic concentrations (see Therapeutic Window, below).
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If it is important to maintain a concentration above the minimum therapeutic level at all times, either a larger dose is given at long intervals or smaller doses at more frequent intervals. If the difference between the toxic and therapeutic concentrations is small, then smaller and more frequent doses must be administered to prevent toxicity.
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If the therapeutic concentration must be achieved rapidly and the Vd is large, a large loading dose may be needed at the onset of therapy. This can be calculated from the following equation:
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Note that clearance does not enter into this computation. If the loading dose is large (Vd much larger than blood volume), the dose should be given slowly to prevent toxicity due to excessively high plasma levels during the distribution phase.