THERAPEUTIC DRUG MONITORING

The application of therapeutic drug monitoring to optimization of drug therapy in individual patients should be considered an adjunct to the physician's clinical judgment in assessing the course and effectiveness of treatment. If the serum drug concentration does not fit the clinical picture, it may be that the effects of disease and age or drug interactions are responsible for alterations in the pharmacokinetic disposition of the drug. Knowledge of the drug's pharmacokinetic profile is important to interpretation of results. For drugs with a well-defined clinical response, small intra- and interindividual variability, and a high therapeutic index (ie, low toxicity), there is little need for therapeutic drug monitoring. This is especially true for acute or short-term drug therapy where there is no advantage to monitoring drug levels. For treatment of chronic disorders, such as antihypertensive therapy, if the desired response can be readily assessed by a noninvasive technique, such as blood pressure monitoring, there is a low cost/benefit ratio to serial drug monitoring. For other drugs, where there are poor dose-response relationships, optimal therapeutic efficacy requires individualized dosing based on the laboratory measurement of serum drug concentrations. To be effective, however, a correlation must exist between serum concentrations of the drug and the desired pharmacologic effect (ie, a well-documented therapeutic range). Drugs which have a narrow therapeutic window and a low therapeutic index may exhibit toxicity at concentrations close to the upper limit of the therapeutic range and are good candidates for clinical monitoring.

Pharmacokinetic Concepts and Terminology

The time course following administration of a drug is characterized by individualized patterns of absorption, distribution, metabolism, and elimination. Absorption is defined as the crossing of drugs through various sites (intestines, muscle, etc) into the circulatory system. For oral administration, absorption takes place in the gastrointestinal (GI) tract. Drugs with limited solubility, such as phenytoin, may be poorly absorbed from the GI tract and may result in low serum levels. Most orally administered drugs are rapidly absorbed and reach peak serum concentrations within 1-2

hours (see Figure 1).

The drug distribution phase is the time required for the drug to penetrate and equilibrate with its site of action and other extravascular tissues. The pharmacokinetic term used to express the apparent volume of distribution is its Vd. The Vd is calculated by dividing administered drug dose by the actual serum drug concentration achieved. This volume does not necessarily pertain to a physiological space but is conceptually regarded as a single body compartment to account for all drug within the body (see Equation 1). Vd = dose [serum]

A drug's volume of distribution is inversely proportioned to the degree of plasma protein binding. Drugs such as warfarin and ibuprofen which are extensively bound to plasma proteins (>97%) have a very low Vd. The degree of plasma protein binding has a significant impact on drug distribution and the pharmacologic activity of the drug. The total drug concentration in plasma is comprised of protein-bound drug, bound to proteins such as albumin and alpha-1-acid glycoprotein, and drug that is unbound, or free. It is the free drug that is physiologically active and exerts a pharmacologic effect. The protein-bound drug is inactive because conformationally it is too large a molecule to cross cell membranes and bind with drug receptor sites at the target organ. Alterations in the degree of plasma protein binding by drug interactions, age, and disease can completely change our interpretation of drug levels and their biological effect. An excellent review of these phenomena has been presented by Cross and Longa.1

Metabolism and elimination determine the duration of the drug's pharmacologic activity and are the result of biotransformations that take place primarily within the liver and are followed by excretion by the kidneys. Drugs undergo hepatic metabolism to produce more soluble forms as a means of detoxification and subsequent elimination through renal excretion. Clearance of a drug by glomerular filtration is reduced in patients with decreased renal function and will affect the biologic or elimination half-life t1/2 of the drug. The t1/2 is the time required to reduce the plasma concentration by one-half. Increases in half-life caused by disease and age or drug interactions will significantly effect serum drug levels and may produce toxicity in patients if the amount of the dose and the dosing schedule is not appropriately modified. Steady-state drug concentrations provide the best correlation between serum drug concentrations and clinical status (see Figure 2). At steady-state the amount of drug being eliminated from the body is equal to the amount administered. The steady-state drug concentration is usually achieved after three to five half-lives of a given drug. Loading doses circumvent the necessity of waiting three to five half-lives to achieve a maximum therapeutic effect.

The dosing interval and the biologic half-life determine the extent of drug accumulation. As seen from Figure 3, patients receiving a drug at a dosing interval longer than the halflife of the drug will exhibit large fluctuations between the peak and trough levels. Shorter intervals lead to less variation. To be effective the serum concentration must be

maintained within the therapeutic range for the drug.

The therapeutic range is defined as the range of serum drug concentrations associated with the desired therapeutic effect and a low risk of toxicity in the majority of patients. Some patients may require serum levels exceeding the upper limit and some below the lower limit to realize optimum benefit from the drug. The therapeutic range should be viewed only as a guide to establishing the appropriate serum concentration for each patient.

Timing of Specimen Collection

Ideally, for therapeutic drug monitoring, the specimen should be collected after the absorption and distribution phases are complete and steady-state has been achieved. Drug levels obtained before steady-state has been achieved could be interpreted improperly as being subtherapeutic and prompt an increase in dosage. This could result in toxicity. For routine serum monitoring of drugs with short half-lives, such as the aminoglycosides, both a steady-state peak and trough level should be obtained. Refer to the specific drug for collection of peak levels. Trough levels are collected just prior to the next dose. For drugs with a long half-life, steady-state trough levels provide sufficient clinical information. To determine possible toxicity, a specimen collected at any time following administration of the drug is generally adequate. To determine half-life at least two specimens should be collected after the peak sampling interval and before administration of the next dose. Half-lives may be helpful in establishing possible toxicity and the need for therapeutic intervention.

Altered Pharmacokinetics

In vivo disposition of drugs varies with age and disease and with drug-drug interactions. These factors are responsible for the intra- and interindividual variations encountered and make sound clinical interpretation a scientific challenge.

Age
There are age-related pharmacokinetic differences among the neonate, infant, child, pubescent child, adult, and geriatric adult that can be attributed to changing metabolic functions and protein-binding characteristics. Metabolic rates and metabolic pathways for microsomal enzymatic biotransformations and clearance of drugs change significantly as a newborn infant matures. Neonates clear drugs very slowly, progressing to much faster in infants and children as compared to adults. For example, approximately 25% of a dose of theophylline is metabolized to caffeine in the neonate, while this pathway is insignificant in children and adults.2 As a general rule of thumb, children metabolize drugs twice as fast as adults and need higher maintenance doses to obtain the same therapeutic effect. As a child enters puberty, the rate may slow abruptly and drug levels should be monitored carefully to avoid toxicity. In geriatric patients, drugs are cleared at a slower rate than adults due to a combination of decreasing metabolic activity and the onset of reduced renal function. Dosages must be scaled back to account for these alterations in drug disposition in order to avoid toxicity. Drugs that are highly bound to serum proteins are affected significantly by changes in protein concentration or binding affinities. Any factor that disturbs the equilibrium between bound and free drug will exert a pharmacologic effect as the % free is increased or decreased. For example, neonates have a higher % free of phenytoin because of displacement by unconjugated bilirubin at albumin binding sites. The lower therapeutic range for phenytoin in neonates (6-15 g/mL) reflects the higher percentage of biologically active free phenytoin. In geriatric patients who typically have lowered serum albumin concentrations, or patients of any age that have decreased albumin levels because of disease, the % free drug is increased because of the limited number of albumin binding sites. Consequently, these patients should be maintained at lower total drug levels. From Equation 1 it can be seen that the serum concentration is inversely proportional to the Vd. Any changes in the volume of distribution will impact the serum drug level. Increases in body fat will increase the volume of distribution for lipophilic drugs and decrease the volume of distribution for hydrophilic drugs. The converse would be true for decreases in the percentage of body fat.

As people age, total body water decreases, lean body mass is reduced, and the percentage of body fat increases. Lipid-soluble drugs such as desmethyldiazepam, a metabolite of diazepam, are stored in a increasingly larger body compartment. This will temporarily decrease the serum level of the drug and will prolong the half-life from an average of 20 hours at age 20-90 hours at age 803. If the drug is prescribed as a maintenance dose the available lipid binding sites will become saturated and the serum concentration of the drug will begin to increase. Therapeutic monitoring will prevent toxicity from developing.

Disease Processes
Renal glomerular disease reduces the clearance of drugs and drug metabolites and increases its biologic half-life as manifested by an increase in serum concentration. For the aminoglycosides, such as gentamicin and tobramycin, which themselves are nephrotoxic, this can have a significant impact. Protein-losing enteropathies and hyperalbuminuria due to renal glomerular disease will interfere with the normal protein-binding characteristics of the drug and will increase the amount of the pharmacologically active free form. This was alluded to above under AGE. Hepatic disease may lead to hypoalbuminemia and increase the free drug fraction. Also, for those drugs that are cleared by the liver, such as propranolol or lidocaine, reduced cardiac output, as in congestive heart failure, will result in higher serum levels due to reduced hepatic perfusion.

Drug-Drug Interactions
If given a choice, single drug therapy is preferable to multiple drug therapy. The practice of polypharmacy to treat multiple disease processes, especially in elderly patients, creates potential problems in properly interpreting drug levels and adjusting dosage. Whenever another drug is added to the regimen, drug levels should be obtained after three to five half-lives to evaluate possible drug-drug interactions. Examples of drug-drug interactions are abundant in the medical literature. For example, phenytoin, which is usually about 90% protein-bound, is affected by concomitantly prescribed drugs that can displace phenytoin from its albumin attachment. In particular, valproic acid can increase the free fraction of phenytoin by 30% to 100%. Phenytoin toxicity may develop at therapeutic serum concentrations. Monitoring free drug levels would provide more clinically relevant information than total drug levels in cases such as this. Patients on digoxin that are subsequently prescribed quinidine should be closely monitored to avoid possible toxicity. Quinidine decreases the renal clearance of digoxin,

thus prolonging the half-life of digoxin, and this could lead to digitalis toxicity if the dose of digoxin is not reduced.

Footnotes
1. Longa GJ and Cross RE, "Laboratory Monitoring of Drug Therapy. Part II: Variable Protein Binding and Free (Unbound) Drug Concentration,"Bulletin of Laboratory Medicine, 1984, 80:1-6. 2. Thomson AH, "Therapeutic Drug Monitoring in the Neonate,"Syva Monitor, 1993, 11(1):1-5. 3. Jenike MA, "Psychoactive Drugs in the Elderly: Antipsychotics and Anxiolytics,"Geriatrics, 1988, 43(9):53-4. Copyright 2001 by Laboratory Corporation of America Holdings and Lexi-Comp Inc. All Rights Reserved