Therapeutic drug monitoring

Blood or plasma drug concentrations at steady state are typically measured to refine estimates of CL/F for the individual. Updated estimates are then used to adjust maintenance doses to reach the desired target concentration. Drug concentrations can be misleading if the relevant pharmacokinetics (and toxicokinetics, see below) are not considered. In addition, individual variability in drug response, due to multiple drug use, disease, genetic differences, and tolerance must be considered. Pharmacokinetic characteristics of drugs may differ with development and age. Therefore, drug effects may vary considerably between infants, children, and adults. For example, water constitutes 80% of the weight of a newborn whereas in adults it constitutes approximately 60%. These differences effect distribution of drugs throughout the body.

3.1.6.1 Plasma

Measurement of drug concentrations in plasma is the cornerstone of therapeutic drug monitoring (TDM), but it is not without pitfalls. In many instances, clinical response does not correlate with plasma drug concentrations. Other considerations may be as follows.

3.1.6.1.1 Time Delays

It often takes time for a response to reflect a given plasma concentration due to the individual kinetics of the drug. Until this equilibrium is reached, correlation between response and concentration is difficult and may lead to misinterpretation of the clinical picture. Delay may be due to lack of equilibration between plasma and target organ as the drug distributes throughout the body. In addition, delay may be because the response measured is an indirect measure of drug effect, e.g., a change in blood pressure is an indirect measure of either change in peripheral resisitance or cardiac output or both.

3.1.6.1.2 Active Metabolites

Poor correlation may be found between response and plasma concentration of parent drug if active metabolites are present and not measured. Formation of active metabolites may be a function of the route of drug administration because oral ingestion generally produces an initial surge of metabolites due to the first pass effect of the liver compared with drugs administered intravenously.

3.1.6.1.3 Exposure Duration

Some drugs exhibit unusual concentration/response relationships which minimizes the utility of TDM. In these cases, clinical response correlates more with duration of dosing than the actual dose or resultant plasma concentrations.

3.1.6.1.4 Tolerance

The effectiveness of a drug may diminish with continual use. Tolerance denotes a decreased pharmacological responsiveness to a drug. This is demonstrated by several drugs of abuse including ethanol and heroin. The degree of tolerance varies but is never complete. For example, tolerance to the effects of morphine quickly develops, but the user is not totally unresponsive to the pharmacological effects. To compensate for the development of tolerance, the dose is increased. Tolerance may develop slowly, such as in the case of tolerance to the CNS effects of ethanol, or can occur acutely (tachyphylaxis) as in the case of nicotine. In these cases, a correlation may be found between plasma drug concentration and the intensity of response at a given moment, but the relationship is not consistent and varies with time.16

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