Interpretation of Drug Concentration Measurements

INTERPRETATION OF DRUG CONCENTRATION MEASUREMENTS

Clearance

Clearance is the single most important factor determining drug concentrations. The interpretation of measurements of drug con-centrations depends on a clear understanding of three factors that may influence clearance: the dose, the organ blood flow, and the intrinsic function of the liver or kidneys. Each of these factors should be considered when interpreting clearance estimated from a drug concentration measurement. It must also be recognized that changes in protein binding may lead the unwary to believe there is a change in clearance when in fact drug elimination is not altered (see Box: Plasma Protein Binding: Is It Important?). Factors affecting protein binding include the following:

Albumin concentration: Drugs such as phenytoin, salicylates,and disopyramide are extensively bound to plasma albumin. Albumin levels are low in many disease states, resulting in lower total drug concentrations. 

Alpha₁-acid glycoprotein concentration: α₁-Acid glycopro-tein is an important binding protein with binding sites for drugs such as quinidine, lidocaine, and propranolol. It is increased in acute inflammatory disorders and causes major changes in total plasma concentration of these drugs even though drug elimination is unchanged. Capacity-limited protein binding: The binding of drugs toplasma proteins is capacity-limited. Therapeutic concentra-tions of salicylates and prednisolone show concentration-de-pendent protein binding. Because unbound drug concentration is determined by dosing rate and clearance—which is not altered, in the case of these low-extraction-ratio drugs, by pro-tein binding—increases in dosing rate will cause corresponding changes in the pharmacodynamically important unbound concentration. In contrast, total drug concentration will increase less rapidly than the dosing rate would suggest as protein bind-ing approaches saturation at higher concentrations.

Dosing History

An accurate dosing history is essential if one is to obtain maxi-mum value from a drug concentration measurement. In fact, if the dosing history is unknown or incomplete, a drug concentration measurement loses all predictive value.

Timing of Samples for Concentration Measurement

Information about the rate and extent of drug absorption in a particular patient is rarely of great clinical importance. However, absorption usually occurs during the first 2 hours after a drug dose and varies according to food intake, posture, and activity. Therefore, it is important to avoid drawing blood until absorption is complete (about 2 hours after an oral dose). Attempts to mea-sure peak concentrations early after oral dosing are usually unsuc-cessful and compromise the validity of the measurement, because one cannot be certain that absorption is complete.

Some drugs such as digoxin and lithium take several hours to distribute to tissues. Digoxin samples should be taken at least 6 hours after the last dose and lithium just before the next dose (usually 24 hours after the last dose). Aminoglycosides distribute quite rapidly, but it is still prudent to wait 1 hour after giving the dose before taking a sample.Clearance is readily estimated from the dosing rate and mean steady-state concentration. Blood samples should be appropriately timed to estimate steady-state concentration. Provided steady state has been approached (at least three half-lives of constant dosing), a sample obtained near the midpoint of the dosing interval will usually be close to the mean steady-state concentration.

Plasma Protein Binding: Is It Important?

Plasma protein binding is often mentioned as a factor playing a role in pharmacokinetics, pharmacodynamics, and drug interac-tions. However, there are no clinically relevant examples of changes in drug disposition or effects that can be clearly ascribed to changes in plasma protein binding (Benet & Hoener, 2002). The idea that if a drug is displaced from plasma proteins it would increase the unbound drug concentration and increase the drug effect and, perhaps, produce toxicity seems a simple and obvious mechanism. Unfortunately, this simple theory, which is appropri-ate for a test tube, does not work in the body, which is an open system capable of eliminating unbound drug.

First, a seemingly dramatic change in the unbound fraction from 1% to 10% releases less than 5% of the total amount of drug in the body into the unbound pool because less than one third of the drug in the body is bound to plasma proteins even in the most extreme cases, eg, warfarin. Drug displaced from plasma protein will of course distribute throughout the volume of distribution, so that a 5% increase in the amount of unbound drug in the body produces at most a 5% increase in pharmacologically active unbound drug at the site of action.

Second, when the amount of unbound drug in plasma increases, the rate of elimination will increase (if unbound clear-ance is unchanged), and after four half-lives the unbound con-centration will return to its previous steady-state value. When drug interactions associated with protein binding displacement and clinically important effects have been studied, it has been found that the displacing drug is also an inhibitor of clearance, and it is the change in clearance of the unbound drug that is the relevant mechanism explaining the interaction.

The clinical importance of plasma protein binding is only to help interpretation of measured drug concentrations. When plasma proteins are lower than normal, then total drug concen-trations will be lower but unbound concentrations will not be affected.

Initial Predictions of Volume of Distribution & Clearance

A. Volume of Distribution

Volume of distribution is commonly calculated for a particular patient using body weight (70-kg body weight is assumed for the values in Table 3–1). If a patient is obese, drugs that do not read-ily penetrate fat (eg, gentamicin and digoxin) should have their volumes calculated from fat-free mass (FFM) as shown below. Total body weight (WT) is in kilograms and height (HTM) is in meters:

Patients with edema, ascites, or pleural effusions offer a larger volume of distribution to the aminoglycoside antibiotics (eg, gen-tamicin) than is predicted by body weight. In such patients, the weight should be corrected as follows: Subtract an estimate of the weight of the excess fluid accumulation from the measured weight. Use the resultant “normal” body weight to calculate the normal volume of distribution. Finally, this normal volume should be increased by 1 L for each estimated kilogram of excess fluid. This correction is important because of the relatively small volumes of distribution of these water-soluble drugs.

B. Clearance

Drugs cleared by the renal route often require adjustment of clear-ance in proportion to renal function. This can be conveniently estimated from the creatinine clearance, calculated from a single serum creatinine measurement and the predicted creatinine pro-duction rate.

The predicted creatinine production rate in women is 85% of the calculated value, because they have a smaller muscle mass per kilogram and it is muscle mass that determines creatinine pro-duction. Muscle mass as a fraction of body weight decreases with age, which is why age appears in the Cockcroft-Gault equation.

Revising Individual Estimates of Volume of Distribution & Clearance

The commonsense approach to the interpretation of drug concen-trations compares predictions of pharmacokinetic parameters and expected concentrations to measured values. If measured concen-trations differ by more than 20% from predicted values, revised estimates of V or CL for that patient should be calculated using equation (1) or equation (2). If the change calculated is more than a 100% increase or 50% decrease in either V or CL, the assump-tions made about the timing of the sample and the dosing history should be critically examined. For example, if a patient is taking 0.25 mg of digoxin a day, a clinician may expect the digoxin concentration to be about 1 ng/ mL. This is based on typical values for bioavailability of 70% and total clearance of about 7 L/h (CL_renal 4 L/h, CL_nonrenal 3 L/h). If the patient has heart failure, the nonrenal (hepatic) clearance might be halved because of hepatic congestion and hypoxia, so the expected clearance would become 5.5 L/h. The concentration is then expected to be about 1.3 ng/mL. Suppose that the concentra-tion actually measured is 2 ng/mL. Common sense would suggest halving the daily dose to achieve a target concentration of 1 ng/mL. This approach implies a revised clearance of 3.5 L/h. The smaller clearance compared with the expected value of 5.5 L/h may reflect additional renal functional impairment due to heart failure.This technique will often be misleading if steady state has not been reached. At least a week of regular dosing (three to four half-lives) must elapse before the implicit method will be reliable.