Dosage regimens

Pharmacokinetic principles, in addition to clinical factors such as the state of the patient, are utilized in determining dosage regimens. Factors that relate to the safety and efficacy of the drug such as activity-toxicity relationships (therapeutic window and side effects), and pharmaceutical factors, such as dosage form and route of administration, must be considered.16

The goal of a therapeutic regimen is to achieve therapeutic concentrations of a drug continuously or intermittently. The latter is useful if tolerance to the drug develops, or if the therapeutic effects of the drug persist and increase in intensity even with rapid drug disappearance. Adjustments to the dosage regimen are made to maintain therapeutically effective drug concentrations and minimize undesirable effects. Optimization of drug therapy is typically determined empirically; that is changing the dose based on response of the individual. However, there is often better correlation between blood or plasma concentration or amount of drug in the body than the dose administered. Therefore, pharmacokinetic data is useful in the design of dosage regimens. In theory, data following a single dose may be used to estimate plasma concentrations following any dosing design.

For drugs whose effects are difficult to measure, or whose therapeutic index is low, a target level or steady state plasma concentration is desirable. A dose is computed to achieve this level, drug concentrations are measured, and the dose is adjusted accordingly. In order to apply this strategy, the therapeutic range should be determined. For many drugs the lower limit of this range appears to be the concentration that produces 50% maximal response. The upper limit is determined by drug toxicity and is commonly determined by the concentration at which 5 to 10% of patients experience a toxic effect.3 The target concentration is then chosen at the middle of the therapeutic range.

3.1.5.1 Loading Doses

The loading dose is one or a series of doses that are administered at the beginning of therapy. The objective is to reach the target concentration rapidly. The loading dose can be estimated with the following formula:

Loading Dose = Target Cp x Vss/F

where

Cp = Concentration in plasma

V ss= Volume of Distribution at steady state F = Fractional bioavailability of the dose

A loading dose is desirable if the time to achieve steady state is long compared to the need for the condition being treated. One disadvantage of a loading dose is the acute exposure to high concentrations of the drug which may result in toxic effects in sensitive individuals.

3.1.5.2 Dosing Rate

In the majority of clinical situations, drugs are administered as a series of repeated doses or as a continuous infusion in order to maintain a steady state concentration. Therefore, a maintenance dose must be calculated such that the rate of input is equal to the rate of drug loss. This may be determined using the following formula:

Dosing Rate = Target x CL/F

where

CL= Clearance

F= Fractional bioavailability of the dose

It is obvious from the above that in order to design an appropriate dosage regimen, several pharmacokinetic factors, including CL, F, Vss, and half-life, must be known in addition to an understanding of the principles of absorption and distribution of the drug in question. The clinician must also be aware of variations in these factors in a particular patient. One should note that even "normal" individuals exhibit variations in these parameters. For example, one standard deviation on clearance values may be 50%. These unpredicted variations in pharmacokinetic parameters may result in a wide range of drug concentrations. This is unacceptable in most cases especially for those drugs with a low therapeutic index. Therefore, Cp should be measured and estimates of CL, F, and Vss calculated directly.

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