Target Concentration Intervention: Application of Pharmacokinetics & Pharmacodynamics to Dose Individualization

TARGET CONCENTRATION INTERVENTION: APPLICATION OF PHARMACOKINETICS & PHARMACODYNAMICS TO DOSE INDIVIDUALIZATION

The basic principles outlined above can be applied to the interpre-tation 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 addi-tion, it may be necessary to consider two pharmacodynamic vari-ables: 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.)

Pharmacokinetic Variables

A. Absorption

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.

The Target Concentration Strategy

Recognition of the essential role of concentration in linking pharmacokinetics and pharmacodynamics leads naturally to the target concentration strategy. Pharmacodynamic princi-ples 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 pharmacoki-netic principles to arrive at a suitable dosing regimen (Holford, 1999). The target concentration strategy is a process for opti-mizing the dose in an individual on the basis of a measured surrogate response such as drug concentration:

Choose the target concentration, TC.

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.

Give a loading dose or maintenance dose calculated from TC, V, and CL.

Measure the patient’s response and drug concentra-tion.

Revise V and/or CL based on the measured concentra-tion.

Repeat steps 3–5, adjusting the predicted dose to achieve TC.

Overdosage and underdosage relative to the prescribed dosage—both aspects of failure of adherence—can frequently be detected by concentration measurements when gross deviations from expected values are obtained. If adherence is found to be adequate, absorption abnormalities in the small bowel may be the cause of abnormally low concentrations. Variations in the extent of bioavailability are rarely caused by irregularities in the manufac-ture of the particular drug formulation. More commonly, varia-tions in bioavailability are due to metabolism during absorption.

B. Clearance

Abnormal clearance may be anticipated when there is major impairment of the function of the kidney, liver, or heart. Creatinine clearance is a useful quantitative indicator of renal function. Conversely, drug clearance may be a useful indicator of the func-tional consequences of heart, kidney, or liver failure, often with greater precision than clinical findings or other laboratory tests. For example, when renal function is changing rapidly, estimation of the clearance of aminoglycoside antibiotics may be a more accurate indicator of glomerular filtration than serum creatinine.

Hepatic disease has been shown to reduce the clearance and prolong the half-life of many drugs. However, for many other drugs known to be eliminated by hepatic processes, no changes in clearance or half-life have been noted with similar hepatic disease. This reflects the fact that hepatic disease does not always affect the hepatic intrinsic clearance. At present, there is no reliable markerof hepatic drug-metabolizing function that can be used to predict changes in liver clearance in a manner analogous to the use of creatinine clearance as a marker of renal drug clearance.

C. Volume of Distribution

The apparent volume of distribution reflects a balance between binding to tissues, which decreases plasma concentration and makes the apparent volume larger, and binding to plasma pro-teins, which increases plasma concentration and makes the appar-ent volume smaller. Changes in either tissue or plasma binding can change the apparent volume of distribution determined from plasma concentration measurements. Older people have a relative decrease in skeletal muscle mass and tend to have a smaller appar-ent volume of distribution of digoxin (which binds to muscle proteins). The volume of distribution may be overestimated in obese patients if based on body weight and the drug does not enter fatty tissues well, as is the case with digoxin. In contrast, theophyl-line has a volume of distribution similar to that of total body water. Adipose tissue has almost as much water in it as other tis-sues, so that the apparent total volume of distribution of theophyl-line is proportional to body weight even in obese patients.

Abnormal accumulation of fluid—edema, ascites, pleural effusion—can markedly increase the volume of distribution of drugs such as gentamicin that are hydrophilic and have small vol-umes of distribution.

D. Half-Life

The differences between clearance and half-life are important in defining the underlying mechanisms for the effect of a disease state on drug disposition. For example, the half-life of diazepam increases with patient age. When clearance is related to age, it is found that clearance of this drug does not change with age. The increasing half-life for diazepam actually results from changes in the volume of distribution with age; the metabolic processes responsible for eliminating the drug are fairly constant.

Pharmacodynamic Variables

A. Maximum Effect

All pharmacologic responses must have a maximum effect (E_max). No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved.

If increasing the dose in a particular patient does not lead to a further clinical response, it is possible that the maximum effect has been reached. Recognition of maximum effect is helpful in avoid-ing ineffectual increases of dose with the attendant risk of toxicity.

B. Sensitivity

The sensitivity of the target organ to drug concentration is reflected by the concentration required to produce 50% of maxi-mum effect, the C ₅₀. Diminished sensitivity to the drug can be detected by measuring drug concentrations that are usually asso-ciated with therapeutic response in a patient who has not responded. This may be a result of abnormal physiology—eg, hyperkalemia diminishes responsiveness to digoxin—or drug antagonism—eg, calcium channel blockers impair the inotropic response to digoxin.

Increased sensitivity to a drug is usually signaled by exaggerated responses to small or moderate doses. The pharmacodynamic nature of this sensitivity can be confirmed by measuring drug concentrations that are low in relation to the observed effect.