Therapeutic drug monitoring (Proceedings)
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. However, a therapeutic range (Cmin and Cmax ) is a population parameter that describes the range between which 95% of the animals might respond. Response below the therapeutic range does not necessarily indicate therapy is not needed; likewise, failure should not be considered only if the drug is above the maximum range. For some patients, the maximum range will need to be exceeded and should be considered if the drug is safe and respon. Thus, the absence of seizures in a dog with subtherapeutic concentrations is not justification for discontinuing the drug. On the other hand, a very small proportion of animals respond at concentrations higher than the recommended maximum and risk-benefit considerations should determine the need to add a second drug.
Marked inter-individual variability in physiology, response to disease and response to drugs results in variability in dose-response relationships. The most recent examples are Collie breeds with the MDR gene mutation, and drug interactions involving CYP3A4 or P-glycoprotein. Changes in drug metabolism and excretion induced by age, sex, disease or drug interactions are among the more important factors which can cause PDC to become higher or lower than expected. Therapeutic drug monitoring replaces the trial and error approach to dosing regimen designs that may prove costly both financially and to patient health. 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 due 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 [or diet] interactions. 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, antibimicrobials, 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; [TPH], or phenobarbital [PB] in cats); 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, PB); 5) non-linear pharmacokinetics which may lead to rapid accumulation of drugs to toxic concentrations (eg, phenytoin or, in cats, PB); and an unexpected toxicity due to drug interactions (eg, enrofloxacin induced TPH toxicity or chloramphenicol or clorazepate induced PB 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. 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. Rather, all active metabolites and/or the parent drug should be measured. For cyclosporine (CsA), for which parent and some metabolites are active, HPLC measures only the parent whereas immunoassays measure parent and some metabolites. For many drugs, recommended therapeutic ranges in animals have been extrapolated from those determined in humans, but care must be taken for this approach (eg, bromide and procainamide). 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. Cost of the analytical method must be reasonable.
Implementation and response to TDM requires an understanding of the relationships between PDC, interval (T) and drug elimination half-life [t½]. In general, TDM should not be implemented until PDC have reached steady state in the patient. Steady-state PDC occur at the point when drug input and drug elimination (ie, distribution, metabolism and/or excretion) are equilibrated. Although PDC change to some degree during the dosing interval, they remain constant between intervals at steady-state (note that "steady-state is not actually reached with drugs whose half-life [ t½] is substantially shorter than the dosing interval). With multiple drug dosing at the same regimen, PDC will reach 50, 75 and 87.5% of steady-state concentration at one, two or three half-lives, respectively (and so on) regardless of the drug. The same time period (ie, 3-5 drug half-lives) must elapse prior to monitoring if any portion of the original dosing range (ie, dose, frequency or route) is changed. For drugs with a long t½, compared to the dosing interval, drug accumulation can be very dramatic (ie, the drug concentrations following the first dose (PDCfirst) are much lower than drug concentrations at steady state (PDCss). 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. The amount that the drug accumulates depends on how much shorter the interval is compared to the t½ (ratio of T: t½). For drugs characterized by a long t½, TDM can be implemented by measuring concentrations at approximately one drug t½ at which time PDC will be approximately 50% of PDCss. 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. After a loading dose is administered, the maintenance dose should be "just right" to maintain PDC achieved after loading. If not, a problem may not become obvious until steady-state occurs (ie, 3 to 5 t½; for bromide, this would be 3 months). However, monitoring can be used to pro-actively evaluate the proper maintenance dose. When using a loading dose, TDM might be performed three times. Using bromide as an example, the first time is after oral absorption of the last dose of the loading dose is complete to establish a baseline (eg, day 6). The second time would be one drug t½ later (eg, 21 days), to assure that the maintenance dose is able to maintain concentrations achieved by loading. One drug t½ later is recommended because most of the change in drug concentrations that will occur if the maintenance dose is not correct will be present at this time. If the second sample (collected at one drug t½) 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. In general, monitoring of a drug with a long half-life requires only one sample. Generally, for consistency's sake, we suggest collection of a trough (before the next dose).