INTRODUCTION

"If we continue in the practice of 'one dose for all' we all quickly enter unmanaged chaos and total irrationality." Dr. Jerome Schentag, New York State University at Buffalo, NY

Medical treatment is often the last act in the process of managing a disease in animals. Drug treatment consists on the selection of an appropriate drug and its delivery at the adequate dosage regimen. The latter implies an adequate dose, route, frequency, and duration of treatment. The ultimate objective of drug therapy is the acquisition of optimal drug concentrations at the site of action that ensure the best support possible to the body's defense and homeostatic mechanisms in order to overcome the pathologic process affecting the individual patient. A basic knowledge of the principles of drug disposition will facilitate the selection of appropriate dosage regimens. In this paper we will discuss the use of therapeutic drug monitoring (TDM) as a tool that can be of help to the clinician in determining effective and safe dosage regimens of selected drugs for medical therapy of individual patients.

TARGET CONCENTRATION AND THERAPEUTIC WINDOW

The definition of optimal drug concentration varies depending on the pharmacodynamic features of the particular drug. For example, for time-dependent antibiotics like penicillin, optimal therapy is likely related to achieving peak concentration to MIC (minimum inhibitory concentration) ratios of 2-4 and a time above the MIC equal to 75% of the dose interval. For concentration-dependent antibiotics like gentamicin, efficacy seems to be related to obtaining peak concentration to MIC ratios of about 8-10. Whatever the case, drug therapy aims at obtaining target concentrations in plasma (which often reflect the concentrations at the site of action) within the limits of a 'therapeutic window.' This has been previously determined attending at the pharmacokinetic, pharmacodynamic and toxicity profiles of the drug in the target species. The width of this window varies for different drugs and species. When the difference between the minimum efficacious concentration and the minimum toxic concentration is small (2 to 4-fold) the therapeutic window will be referred to as narrow. In contrast, when there are large differences between the effective and toxic concentrations, we'll talk about a wide therapeutic window. An example of a drug with a narrow therapeutic window is digoxin, in which the difference between the average effective and toxic concentrations is 2 or 3-fold. Amoxicillin, on the other hand, has a wide therapeutic range and overdosing of patients doesn't usually lead to toxicity problems.

VARIABILITY IN DRUG DISPOSITION

Variability is a fact of life and as such it also extends to the disposition of drugs. Marked interindividual variability in healthy subjects of the same species is typical in the disposition of many drugs. Furthermore, disease states have the potential to affect organ systems and functions (e.g., kidney, liver, water content...) that may in turn affect drug disposition. This contributes to increase the interindividual variability in sick individuals, which are the recipients of the drug. Finally, when patients receive more than one drug pharmacokinetic interactions may occur by virtue of which the disposition of one or both drugs is altered. In summary, physiological (e.g., age), pathological (e.g., disease effects), and pharmacological (e.g., drug interaction) factors can alter the disposition of drugs in animals. The increased interindividual variability may result in therapeutic failure or toxicity in drugs with a narrow therapeutic index.

Figure 1. The effect of pharmacokinetic variability on the width of the therapeutic window. MTC: minimum toxic concentration in the 90^th percentile. MEC: minimum effective concentration in the 90^th percentile.

As depicted in Figure 1, the combination of narrow therapeutic window and high pharmacokinetic variability can lead to toxicity or lack of efficacy in a certain proportion of the treated population. In this figure, prediction interval lines that represent the disposition in the 10th and 90th percentiles of the population flank the average concentration-time profile. Under the depicted conditions, the uncertainty of the concentration-time predictions can be high enough to cause major potential problems.

THERAPEUTIC DRUG MONITORING

The goal of TDM is to optimize a patient's clinical outcome by managing their medication regimen with the assistance of measured drug concentrations. TDM is based on the assumption that there is a definable relationship between dose and plasma concentration and between the latter and the pharmacological effect. TDM aims at identifying, in the individual patient, the dosage regimen that leads to attaining the concentration that is known to be associated with efficacy and not toxicity. However, there may be substantial interindividual pharmacodynamic variability at a given plasma concentration and therefore a range of concentrations rather than a single level is usually targeted. Population pharmacokinetics and pharmacodynamics, with their ability to account for the sources of interindividual variability can contribute to defining individual-specific concentration targets. In general, TDM might be useful in the following clinical situations:

1.  When starting a new drug regimen of a narrow therapeutic index drug to verify that the appropriate concentration is achieved. E.g., gentamicin in horses.

2.  When the medication that you're using is not working because low concentrations are obtained.

3.  When toxicity is suspected due to high concentrations.

4.  When several drugs are administered together and a pharmacokinetic interaction is anticipated that may modify the disposition of the narrow therapeutic index drug.

5.  When it is difficult to relate the drug response to the dose (e.g., lack of efficacy of an antimicrobial can be due to under dosing or to bacterial resistance).

6.  When the manifestations of the disease are life threatening.

7.  In patients with liver or renal disease.

8.  In young or old animals when disposition is dependent on age.

9.  When assessment of compliance with drug regimen is important

10.  After modification of dosage regimen based on TDM or other evidence

11.  When the drug has a steep concentration-response curve, so that small increases in dose can result in a large increase in pharmacologic and toxic effect

12.  When nonlinear pharmacokinetics leading to drug accumulation apply in particular if chronically used.

13.  When drug is very expensive and the objective is minimizing dose and duration (e.g., cyclosporine)

In general, TDM is most useful when steady-state concentrations have been achieved in the animal. Whether the drug administration is continuous (e.g., infusion) or by multiple dosing, approximately 5 half-lives have to span to reach steady-state. Likewise, when the dosage regimen is modified, a similar amount of time must elapse to achieve the new average steady-state concentration. The number and timing of samples collected during TDM are quite variable. They depend on the pharmacokinetic (i.e., half-life) and pharmacodynamic (e.g., concentration vs. time dependency) features of the drug as well as on the objective of monitoring (i.e., whether the concern is efficacy or toxicity) and the dosage regimen. To illustrate these differences we will briefly review the cases of phenobarbital and gentamicin.

Phenobarbital is a barbiturate drug that is administered orally in dogs twice a day for the long-term treatment of seizure disorders. Half-life ranges between 35 and 75 hours and typically decreases after long-term exposure due to self-induction of microsomal metabolism. The objective of TDM is to ensure that the target plasma concentration is reached. Monitoring of this drug is common after several months of use or when relapse of the epileptic condition is apparent. Relapse may be due to decreased concentrations associated to increased drug metabolism. Keeping concentration oscillations to a minimum is a common objective when monitoring drugs. However, this is not essential with phenobarbital given its long half-life. Peak and trough concentrations are not likely to differ substantially. Therefore, a single sample (usually a trough) is generally sufficient for this drug when the objective of TDM is routine recheck. However, when TDM is conducted at the beginning of therapy or for a patient that is not responding to therapy, peak (5 hr after dose) and trough (right before next dose) samples will be necessary to gain appropriate insight into the half-life of the drug.

Gentamicin is an aminoglycoside antibiotic with a narrow therapeutic index and a short half-life (1-2 hr) that is commonly used to treat infections by Gram (-) bacteria. This is a concentration-dependent antibiotic, whose antimicrobial efficacy seems to be highest when peak concentrations are 5-10 times the bacterial MIC. Toxicity seems to be associated to trough concentrations (at 6-8 hours after dose) not higher than 2 mg/L. Although controlling oscillations in the plasma concentrations might be an obvious objective for TDM of this drug, this will depend on the dose interval. When gentamicin is administered IV at 8 hour intervals, peak (2 hr) and trough (8 hr) samples are necessary to assess both efficacy and safety. When the drug is administered once a day there may be little need for monitoring peak concentrations, for they will usually be well above the required range. Trough concentrations in this case are no longer valid either, for at 24 hours concentrations will not be detectable, and they are usually substituted by a 6-8 hour sample. Nevertheless, therapeutic ranges are not been clearly established for once a day dosing. In any case, when the objective of TDM is determining the half-life of the drug, at least a peak and a trough will be necessary.

Interpretation of TDM plasma concentrations and subsequent dosage regimen adjustment will depend on the drug, the context of the clinical patient and the objective of TDM. Several examples will be reviewed during the lecture presentation.