Therapeutic Drug Monitoring - Auburn University - College of Veterinary Medicine

THERAPEUTIC DRUG MONITORING
Dawn Merton Boothe, DVM, MS, PhD*
From the Department of Veterinary Physiology and Pharmacology*.
The Texas Veterinary Medical Center, College of Veterinary Medicine,
Texas A&M University, College Station, TX 77843-4466.

WHAT IS THERAPEUTIC DRUG MONITORING?

Therapeutic drug monitoring (TDM) is a tool that can guide the clinician to provide effective and safe drug therapy in the individual patient. Monitoring can be used to confirm a plasma drug concentration which is above or below the therapeutic range, thus minimizing the time which elapses before corrective measures can be implemented in the patient (Wilson, 1987; Neff-Davis, 1988; Pippinger, 1984). Understanding the principles of drug disposition and factors which determine these principles in the individual patient will facilitate an understanding of the use of and need for therapeutic drug monitoring.

WHY USE THERAPEUTIC DRUG MONITORING?

The success of any fixed dosing regimen most often is based on the patient's clinical response to the drug. Fixed dosing regimens are designed to generate plasma drug concentrations (PDC) within a therapeutic range, ie, achieve the desired effect while avoiding toxicity. Recommended dosing regimens have proven most successful when based on scientific, pharmacokinetic studies which have been performed in a population of normal, adult animals of the target species intended to receive the drug. However, marked inter-individual variability (within a species) has been confirmed for many drugs (Arnsdorf 1989; Ravis 1984). More importantly, rarely does the patient receiving the drug meet the above criteria. Rather, the patient usually is diseased and its illness often requires treatment with more than one drug. The factors which determine drug disposition are all amenable to change in the unhealthy patient. Physiologic, pathologic and pharmacologic factors can profoundly alter the disposition of a drug such that therapeutic failure or adverse reactions occur. Changes in drug metabolism and excretion induced by age (Cowan 1980), sex, disease (Atkins 1989; Frazier 1987 and 1988; Dunbar 1983) or drug interactions (Ravis 1984; Ravis 1987; Atkins/Snyder, 1988; DeRick 1981) are among the more important factors which can cause PDC to be higher or lower than expected. Recommended dosing regimens are sometimes designed to compensate for the effects of some of these factors. Examples include many feline dosing regimens (eg, aspirin, some selected antimicrobials, etc.); the use of body surface area rather than body weight for drugs with high potential of toxicity (eg, anticancer drugs); and allometric scaling for exotic species. Unfortunately, the effects of many factors are unpredictable and cannot be anticipated in the individual patient, despite innovated dosing calculations.

If the response to the drug by the patient is perceived as inappropriate either due to failure or toxicity, a trial and error approach is used for modifying the dose. If sub-therapeutic concentrations are suspected, the dose or frequency is empirically increased until an adequate response occurs. If a response is still not evident, the cycle may be repeated with a new drug or drug combinations until all reasonable alternatives are exhausted and the illness is then considered refractory to treatment. On the other hand, dosing regimens which induce toxic signs are decreased until signs of toxicity resolve, although therapeutic failure then may occur. Such a trial and error approach to dose modification is appropriate when response to the drug can be easily measured. Examples include "to affect" drugs such as gas inhalant and ultrashort thiobarbiturate anesthetics, rapidly acting anticonvulsants such as diazepam, and lidocaine for the treatment of ventricular arrhythmias. Trial and error can also be used for illnesses that are not serious or do not require immediate resolution and for drugs characterized by large therapeutic windows which are generally safe at high doses. However, trial and error modification of dosing regimens can be inefficient and potentially dangerous when: drug response cannot be easily measured; the drug is characterized by a narrow margin of safety; or the patient's condition is life-threatening. For example, lack of response to an antimicrobial might reflect bacterial resistance or simply failure to generate therapeutic antimicrobial concentrations. In life- threatening infections, timing of effective antimicrobial therapy is critical to success; likewise, toxicity must be avoided in a seriously ill patient. While fever or white blood cell counts can be used to monitor response to an antimicrobial in some patients, these parameters are not always abnormal prior to antimicrobial therapy and in the case of life threatening infections, may not change rapidly enough. Using another example, failure to control seizures with an antiepileptic drug may reflect the refractory nature of the seizures or PDC which are subtherapeutic. Differentiating an assumed digoxin-induced adverse reaction from clinical signs of cardiac or other disease is difficult if PDC of digoxin are not known. Geriatric and pediatric patients represent age extremes for which TDM may prove beneficial (Gal, 1988).

WHEN SHOULD TDM BE USED AND FOR WHICH DRUGS?

Therapeutic drug monitoring is indicated in clinical situations in which an expected therapeutic effect of a drug has not been observed, or in cases where drug toxicity related to high toxic PDC is suspected. In addition, TDM can be used to establish whether or not optimum therapeutic drug concentrations have been achieved for drugs characterized by a response that is difficult to detect or in which the manifestations of disease are life threatening and the trial and error approach to modification of dosing regimen is unacceptable. In situations in which chronic drug administration is expected, TDM can be used to define the effective target PDC in the patient. The target PDC can then be used if pharmacokinetics change in the patient over the course of chronic drug administration due to disease, environmental changes, age or drug interactions (eg, phenobarbital). Drug monitoring has also been useful in identifying owner noncompliance as a cause of therapeutic failure or adverse reactions.

Drugs for which TDM is most useful are characterized by one or more of the following: 1) serious toxicity coupled with a poorly defined or difficult to detect clinical endpoint (eg, anticonvulsants and cyclosporine); 2) a steep dose-response curve for which a small increase in dose can result in a marked increase in desired or undesired response (eg, theophylline); 3) a narrow therapeutic range (eg, digoxin); 4) marked inter-individual pharmacokinetic variability which increases the variability in the relationship between dose and PDC (eg, phenobarbital); 5) non-linear pharmacokinetics which may lead to rapid accumulation of drugs to toxic concentrations (eg, phenytoin or, in cats, phenobarbital); and an unexpected toxicity due to drug interactions (eg, enrofloxacin induced theophylline toxicity or chloramphenicol or clorazepate induced phenobarbital toxicity). In addition, TDM is indicated when a drug is used chronically, and thus is more likely to induce toxicity or changes in pharmacokinetics (ie, anticonvulsants), or in life-threatening situations in which a timely response is critical to the patient (eg, epilepsy or bacterial sepsis). Drugs for which TDM might not be indicated include those characterized by a wide therapeutic index which are seldom toxic even if PDC are higher than recommended, or those for which response can be easily monitored by clinical signs.

Not all drugs can be monitored by TDM; certain criteria must be met (Abbott Laboratories, 1984). Patient response to the drug must correlate with (ie, parallel) PDC. Drugs whose metabolites (eg, diazepam) or for which one of two enantiomers comprise a large proportion of the desired pharmacologic response cannot be as effectively monitored by measuring the parent drug (Drayer, 1988). Rather, all active metabolites and/or the parent drug should be measured. Species differences vary in the production of these metabolites. For example, the efficacy of primidone as an anticonvulsant in dogs and cats reflects its conversion to phenobarbital. Thus phenobarbital is measured. In people, procainamide is metabolized to an active metabolite. Dogs, however, are deficient in this metabolite and thus the parent compound must be measured. An effective therapeutic (C_min) or toxic (C_max) range must have been identified for the drug in the species and for the disease being treated (Arnsdorf, 1989).

For most drugs, recommended therapeutic ranges in animals have been extrapolated from those determined in humans. Controlled clinical trials which establish therapeutic ranges for various diseases generally have not been performed in animals. Yet, therapeutic ranges in the various animal species may differ from people and one another. Procainamide is an example where ranges might differ. Bromide offers another example: concentrations above 1.5 mg/ml might be considered toxic in people but are at the low to mid therapeutic range in dogs. Also, the therapeutic range may differ for the desired response (ie, treatment). The pharmacokinetics of the drug must be established in a large population of animals that receive the drug so that normal ranges are available for the predictive pharmacokinetic parameters. The drug must be detectable in a relatively small serum sample size, and analytical methods must be available to rapidly and accurately detect the drug in plasma (Price, 1984). The methods must be specific for the drug, and be able to differentiate it from other compounds of interest, including metabolites of the drug. Cost of the analytical method must be reasonable. Drugs which meet these criteria and for which TDM has proven useful in veterinary medicine include selected anticonvulsants (phenobarbital, primidone, potassium bromide, selected benzodiazepines), antimicrobials (eg, aminoglycosides, gentamicin, amikacin; others); cardioactive drugs (digoxin, procainamide, lidocaine and quinidine) and theophylline (Table 1). Cyclosporine, an immunomodulating drug, has just recently begun being monitored, behavior modifying drugs (amitryphylline) may join the list as we learn more about these drugs in animals.

HOW IS TDM IMPLEMENTED?

Impact of Drug Elimination Half-life on TDM

In general, TDM should not be performed until PDC have reached steady state in the patient. Steady-state PDC occur at the point when drug input and drug elimination (ie, metabolism and/or excretion) are equilibrated.. Although PDC change to some degree during the dosing interval, they remain constant between intervals at steady-state. With multiple drug dosing, PDC will reach 50% of their steady-state concentration at one half-life; 75% by two half-lives, 87.5%, at three half-lives, and so on. Thus, regardless of the drug, steady-state concentrations are attained only after 4-5 half-lives of a drug administered according to a fixed dosing regimen. The same time period (ie, 4-5 drug half-lives) must elapse for steady-state plasma drug concentrations to be re-established if any portion of the original dosing range (ie, dose, frequency or route) is changed. Evaluation of a drug's efficacy is often inappropriate until steady-state has been reached because it is only then that maximum peak and trough drug concentrations and thus, maximal response will have been achieved. As can be seen from Table 1, the time that must elapse from the start of the dosing regimen until monitoring can take place is quite variable. Depending on the drug half-life in the normal population sample, this time ranges from less than a day to more than three months. For drugs with a long half-life, compared to the dosing interval, drug accumulation can be very dramatic (ie, the drug concentrations following the first dose are much lower than drug concentrations at steady state). The dosing regimen of such drugs is designed such that drug concentrations will be in the therapeutic range, but only when steady state concentrations have been achieved.

Attention to steady-state is important for drugs that accumulate with repetitive dosing. For such drugs, the peak plasma drug concentration is higher at steady-state compared to concentrations following the first dose. At steady-state, the magnitude of increase in PDC at steady-state compared to that after the first dose is referred to as the accumulation ratio. The amount that the drug accumulates depends on how much longer the half-life is compared to the dosing interval. A drug whose half-life is equal to its dosing interval will accumulate 2-fold (ie, at steady-state peak plasma drug concentrations will be twice what they were following the first dose). A drug administered at half the drug elimination half-life will accumulate 4-fold; at one third the drug half-life, accumulation will be 8-fold and so on.

For drugs characterized by a long half-life, TDM can be used during the first several doses to predict peak and trough PDC by calculating the accumulation ratio and subsequently predicted PDC at steady-state. This can be beneficial for drugs whose half-life is so long in a patient that steady-state concentrations will not be achieved for an unacceptably long time. The dose can be modified pro-actively, ie, before steady-state occurs. Example drugs for which this might be beneficial include phenobarbital (half-life up to 5 days; steady-state occurring at 2-3 weeks) and bromide (half-life 24 days, steady-state occurring at 2 to 3 months). Alternatively, concentrations can be measured at approximately one drug half-life (eg, one month for bromide) in order to estimate plasma drug concentrations at steady-state. In either case, the dose can be modified early, rather than waiting for steady state.

A third alternative to proactive monitoring is available for patients for whom steady-state concentrations must be reached immediately. A loading dose can be administered to rapidly achieve therapeutic PDC. The loading dose needed to achieve a known therapeutic concentration of a drug depends upon the V_d of that drug in the patient and the target (ie, the therapeutic concentration: Table 1). If the drug is orally administered, the bioavailability must also be taken into account when the dose is determined. Although a loading dose can decrease the time for maximum response to occur to a drug (by avoiding accumulation to steady state), the hazards of adverse reaction to the drug is much greater. Thus, loading doses are not advised for drugs characterized by a narrow therapeutic index and which tend to cause undesirable adverse reactions (eg, digoxin etc.). However, for safe drugs (eg, bromide, phenobarbital), a loading dose can be administered if deemed appropriate. Even if a loading dose is administered, the maintenance dose may be either too high or too low; the need for maintenance dose modification may not become evident until steady-state occurs (ie, 3 to 5 drug half-lives). When using a loading dose, TDM should be performed after the loading dose is complete to establish a baseline and one drug half-life later (eg, for bromide at 24 to 30 days), to assure that the maintenance dose is able to maintain concentrations achieved by loading. One drug half-life later is recommended because most of the change in drug concentrations will occur at this time if the maintenance dose cannot maintain what the loading dose achieved. If the second sample (collected at one drug half-life) does not approximate the first (collected immediately after the load), the maintenance dose can be modified at this time rather than waiting for steady state and the risk of therapeutic failure or toxicity.

Many drugs are characterized by half-lives that are much shorter than the dosing interval. For these drugs, no to little accumulation occurs, the concept of "steady-state" is perhaps irrelevant, and response can be evaluated with the first dose (or as soon as the disease has had time to respond). For example, many antimicrobials (eg, aminoglycosides) are characterized by a half-life that is less than 2 hours (eg, amikacin in dogs) but are given at a dosing interval of 8-12 hours (Neff-Davis, 1988). Thus 4-6 drug half-lives will have elapsed and less than 5% of the dose will remain in the body by the next dose. With this dosing regimen, amikacin will not accumulate in the plasma and a "steady-state equilibrium" will not be reached. Even though drug concentrations drop below C_min for many of these drugs, the effects of the drug are often still present. For example, aminoglycoside antibiotics are still effective because the post-antibiotic effect exhibited by this and many other antimicrobials allowing a relatively long (and convenient) dosing interval to be used despite the short drug half-life (Bundtzen 1981). Therapeutic drug monitoring is useful in monitoring treatment with these drugs in order to assure that therapeutic concentrations are achieved and toxic concentrations avoided during each dosing interval.

Single versus Two Sample Collection

The number of samples collected for TDM depends on the drug, its elimination half-life and the question to be answered by monitoring (ie, is the dose safe or is it effective). For all drugs, PDC are likely to continue to fluctuate during a fixed dosing interval unless drug half-life is much longer than the dosing interval. The trough PDC is the lowest drug concentration that develops during a dosing interval and it theoretically should not drop below the C_min (the aminoglycosides are an exception). It occurs just prior to administration of the next dose and represents the maximum effect of the processes of drug elimination (ie, metabolism and excretion) that occur between doses. The peak PDC is the maximum concentration achieved after a dose is administered and presumably it should not exceed C_max. For IV drugs, its magnitude is based on the volume of distribution; for oral drugs, its magnitude also is dependent upon the rate and extent of drug absorption. The relationship between peak and trough PDC is determined by drug half-life.

Peak and trough concentrations will be very different from one another for drugs with a short half-life compared to the dosing interval (eg, benzodiazepines, antibiotics, and for some patients, phenobarbital). For such drugs, both a peak and trough sample should be collected. Collection of at least two samples during a single dosing interval is particularly important for drugs characterized by a narrow therapeutic range. For these drugs, effective and toxic drug concentrations are not widely separated and such drugs are more likely to cause adverse reactions. In contrast to drugs with a short half-life, peak and trough concentrations will not differ substantially for drugs whose half-life is much longer than the dosing interval (eg, bromide, and for some patients, phenobarbital) and a single sample is generally sufficient for such drugs. Single samples might also be indicated for slow release products (eg, theophylline) since constant drug absorption mitigates a detectable difference between peak and trough concentrations. Single samples also can be collected following a loading dose (ie, bromide) or at the first half-life (ie, 3 to 4 weeks) in a patient that has just begun bromide therapy. Finally, if the question to be answered by TDM is one of toxicity (eg, digoxin or phenobarbital), a single peak sample may answer the question.

Often times, whether or not the half-life is short or long can only be determined by collecting both a peak and trough sample. For phenobarbital, the elimination half-life may initially be longer than the dosing interval (ie, greater than 48 hours), but following induction (ie, several months into therapy), be much shorter (ie, less than 12 hours) in the same patient. The need for peak and trough samples may not be evident if a long half-life is anticipated. A prudent approach for patients beginning phenobarbital therapy would be to collect peak and trough samples as a baseline, but single samples for rechecks if the patient is responding well to therapy. Peak and trough samples should be collected in any patient that is not responding well to therapy with any drug which may have a short half-life compared to the dosing interval. Digoxin provides a good example of the risk associated with collecting only a single sample when assessing efficacy. Digoxin is characterized by a half-life that ranges from less than 12 hours (thus allowing concentrations to become sub-therapeutic during a dosing interval) to greater than 36 hours (particularly in patients with renal disease). The half-life can change again if the patient responds to therapy for cardiac failure. If toxicity is suspected, a single sample collected at the time that clinical signs of toxicity occur can confirm toxicity. However, neither toxicity no efficacy can be confirmed throughout the dosing interval, unless two samples (peak and trough) are collected.

If a kinetic profile of a patient is the reason for TDM, at least two samples must be collected to establish a PDC versus time curve. The samples preferentially are collected at the peak and trough times unless the interval is so long that drug may not be detectable at the trough time (ie, aminoglycosides administered at 12 or 24 hour dosing intervals). The most accurate kinetic information is generated from patients receiving an IV dose since the volume of distribution can be estimated along with drug elimination half-life. For oral doses, only the rate of elimination and drug half-life can be obtained.

Timing of Sample Collection

Trough samples are generally recommended for consistency across time if single samples are to be collected. Trough samples should be collected as close to but before a dose. Time of peak PDC is more difficult. Peak PDC should be determined after drug absorption and distribution are complete. The route of drug administration can influence the time at which peak PDC occur, which will vary among drugs. For orally administered drugs, absorption is slower (1-2 hours) and distribution is often complete by the time peak PDC have been achieved. However, the absorption rate can vary widely due to factors such as product preparation, the effect of food or patient variability. Obviously, a drug prepared as an elixir will be absorbed more rapidly than the same drug prepared as a capsule or tablet. Because food can slow the absorption of many drugs, fasting is generally indicated (if safe) prior to therapeutic drug monitoring. Generally, peak PDC occur 2-4 hours after oral administration. Some drugs are simply absorbed more slowly than others (eg, phenobarbital) and the time of peak PDC sample collection is longer (eg, 2 to 5 hours for phenobarbital). For drugs administered intravenously, absorption is not a concern but distribution is. For some IM and SC administrations, absorption occurs rapidly (ie, 30-60 minutes), but, again, drug distribution may take longer. Thus, PDC generally are measured 1-2 hours after administration after parenteral drug administration. Exceptions must be made for drugs, such as digoxin, for which distribution may take 6-8 hours. Samples should not be collected for these drugs until distribution is complete (Table 2).

HOW SHOULD TDM SAMPLES BE INTERPRETED?

Information Needed for TDM

The minimum information necessary for interpretation of PDCs includes the following: 1) The total daily dose of drug which will be correlated with the patient's measured PDC. The patient PDC will then be compared to the target concentration and the dose will be modified proportionately. 2) Time intervals of drug administration and sample collection are particularly important for drugs with short half-lives (eg, aminoglycosides). Provision of this information assures the clinical pharmacologist that blood samples contain the actual trough and/or peak drug concentrations. From this data, a drug half-life can be calculated and a proper dosing interval can be determined. 3) The patient's clinical status is important because both acute and chronic diseases can dramatically alter drug disposition patterns. This is particularly true for patients with renal, liver or cardiac disease. If this information is lacking, disease-induced changes in drug disposition cannot be distinguished from other causes such as non-compliance or drug interactions. 4) Concurrently administered drugs may alter drug disposition patterns and thus contribute to individual differences in drug disposition. Frequency, dose, amount and the actual times of all drugs given to the patient must be known in order to recognize or predict potential drug interactions. 5) Physiologic characteristics such as patient species, breed and age are often important to the interpretation of PDC because known or predictable differences they may induce drug disposition, or because of known differences in pharmacodynamic responses. Weight must be provided in order to determine V_d. 6) The reason for TDM should be given, ie, has the patient failed therapy or is the patient exhibiting signs of toxicity?

Dose Modification with Kinetic Calculations

The minimum number of data points needed to develop a pharmacokinetic profile in a patient is two. Generally for TDM, these two samples consist of the peak and trough collected during a single dosing interval. Alternatively, for the sake of convenience, a trough sample can be collected just prior to a dose and the peak sample collected 2 to 5 hours (when appropriate for the drug) following dosing. This protocol assumes that the drug is handled the same way by the body during each dosing regimen. While this is true, conditions such as diurnal variation and treatment can alter drug disposition between dosing intervals. Often, the dose is not the same for both morning and evening. Regardless of when the samples are collected (assuming they are collected after absorption and distribution are complete), when plotted on semilogarithmic paper, the slope between these two points reflects k_el, which is used to determine drug half-life in the patient. Half-life can either be calculated or estimated from the PDC versus time curve drawn on semilog paper. The two points are connected, and the resultant line is extrapolated to both the x and y axis. For estimation, the time that must elapse between any two concentrations on the line where one concentration is twice the second is the half-life. The half-life can be calculated from k_el (the slope, or rise [C₁-C₂] over the run [t₂-t₁]). The line does not need to be plotted to calculate elimination half-life, but the time that each dose was given and each sample was drawn must be known for the calculations (Table 2). Half-life can be used to determine the maximum time that can elapse between doses in the patient before PDC do not fall below the recommended minimum effective concentration during the dosing interval (T_max) (Table 2). The V_d of drugs administered IV can be calculated from the peak PDC and dose (Table 2). If the drug is 100% bioavailable following oral, subcutaneous, or intramuscular administration, V_d can also be estimated from this data. For orally administered drugs for which bioavailability is not known, a population V_d measured in normal animals must be used. However, the individual patient V_d may not be accurately estimated by population V_d. Changes in patient V_d compared to normal animals can be somewhat accommodated for if information regarding patient factors which influence V_d, such as obesity, edema, ascites, dehydration, serum protein concentrations or other factors are known. The V_d is used to calculate the amount of drug which must be administered to achieve C_max, the target (generally maximum) effective drug concentration (loading dose D_L) and the amount of drug necessary to replace drug eliminated during the dosing interval (maintenance dose, D_max) (Table 2). Once D_max and T_maxhave been established, dosing regimens can be appropriately altered to assure that PDC fall within a recommended therapeutic range (Table 2). In addition to calculation of patient pharmacokinetic parameters, another advantage to collecting both a peak and trough drug sample is that the achievement of a minimum effective concentration (C_min) and avoidance concentrations above the maximum (C_max) throughout the dosing interval can be confirmed.

Dose Modification without Kinetics

Not all modifications in dosing regimens require pharmacokinetic calculations. If a patient has drug concentrations outside the therapeutic range, the response is obvious; dose should be modified to bring the drug concentrations into the therapeutic range. Generally, a dose can be modified using the following equation, as long as concentrations were measured at steady-state:

New Dose = Old Dose x (Target PDC/Measured PDC)

New Interval = Old Interval x (Target PDC/Measured PDC)

Modifications of dosing regimens for patients whose drug concentrations are inside the therapeutic range are more problematic. However, the next step becomes more obvious when one remembers that the data reflects the individual patient, whereas a range was established for a sample population. A range reflects the concentrations between which the majority (95%) of the patients are expected to respond. However, for the individual patient, where in the range that patient should be may not be obvious. Therapeutic drug monitoring answers that question. If a patient has not responded, even though "in" the therapeutic range, we stair step drug concentrations gradually until either the patient responds, or the maximum end of the range is reached and the risk of adverse effects becomes too great. We take the same approach, but in the reverse direction if drug concentrations are too high and we want to decrease drug concentrations to a minimum effective dose. The decision as to whether to change the dose or the interval depends upon the drug itself, its therapeutic index, and need to maintain PDC within the therapeutic range throughout a dosing interval. Even if TDM is used to make sure a the PDC stays within a therapeutic range during a dosing interval, a patient may react adversely (including failure to respond therapeutically). Recommended therapeutic ranges generally reflect the range in which a certain percent (ie, 95%) of patients would be expected to respond. Some patients will respond at the low end of the range; some will not respond until the maximum is reached, and a smaller percent of the population will respond at concentrations outside the recommended range. Disease, age and other factors may play a role in the Minimum Effective Concentration (MEC) necessary for each patient. Therefore, it is imperative that plasma drug concentrations be interpreted in conjunction with the desired therapeutic endpoint (ie, complete eradication of seizures versus a decrease in the severity and frequency) as well as the clinical status of the patient. This is particularly important for tests for which there is great overlap between "normal" and "abnormal" ranges (eg, digoxin, thyroid hormones). Many practitioners have available to them instrumentation necessary to monitor phenobarbital and thyroid function.

WHERE IS TDM OFFERED?

Currently, TDM is being offered as an aid to rational drug therapy at several veterinary academic institutions and veterinary diagnostic laboratories throughout North America (Neff-Davis, 1988). The availability of TDM for specific drugs varies with the laboratory. In addition, TDM has received wide acceptance in the human medical field (Goldstein, 1989) and clinical laboratories providing TDM services to human patients may also be amenable to provision of the same services to veterinary practitioners. Note, however, that costs of testing in human patients often far exceeds what pet owners are willing to pay for the same testing in their animal.

If human laboratories are used to determine drug concentrations in animals, therapeutic ranges may differ between animals and people. Examples include clorazepate and bromide. Regardless of the type of laboratory (ie, human and medical), veterinarians should pick laboratories that follow a good quality assurance program. This means that assays which detect drugs have been validated in the species of interest, and controls are used daily or with each test to make sure that the assay is valid. Many veterinary laboratories use automated assays that were designed to measure drugs in humans. To assume that the assays will detect the drug in animals is incorrect. Constituents in plasma differ substantially between species, and these constituents can interfere with the methodology of some assays. Bromide analysis offers a unique concern. The assay (gold chloride method) to accurately detect bromide in serum is tedious and many laboratories do not offer it because it is time consuming. Some laboratories use a bromide sensitive ion probe, which is very easy and can be rapidly performed. Unfortunately, the probes are not able to distinguish high concentrations of bromide (above 1.5 mg/ml) from other ions present at high concentrations in the serum (such as chloride) and manufacturers of the probe may state that the probe should not be used to measure bromide in serum. Because of the inability to accurately detect all concentrations in the therapeutic range, laboratories which use this technique may limit normal values to concentrations which can be accurately detected rather than an actual therapeutic range. Laboratories to be used for monitoring should be contacted prior to use to assure quality control procedures are followed and that assays used in animals have been validated.

Attention should be given as to how the sample collected from the patient is handled. Some drugs may require refrigeration or freezing (Table 3). Sample size may vary for each drug, or even for the same drug depending on the methodology the laboratory uses. Drugs can interact with the containers in which they are collected or mailed. In general, serum separator tubes should not be used to collect or mail samples containing drug. Drugs can bind to the silicon gel which will decrease concentrations measured in blood. Aminoglycosides can bind to glass; samples should be collected and submitted in plastic tubes. The effect of hemolysis and hyperlipidemia on drug assays will vary. In general, it is wise to avoid either in sample collection. Although sample handling is often the same for each drug, the laboratory to which the sample will be submitted should be contacted prior to sending a sample for TDM analysis. Idiosyncrasies regarding timing of sample, collection, and storage apparatus (ie, tubes and anticoagulants), mailing instructions (including conditions) and cost should be known prior to collection.

In summary, TDM can aid clinicians in the titration of drug doses to the individual patient, thus avoiding adverse reactions which are a direct consequence of patient variability in drug disposition. In addition, TDM assures that optimal drug concentrations are established promptly and that therapeutic drug concentrations are maintained, thus avoiding a protracted period of ineffective drug therapy.

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