A case-based approach to therapeutic drug monitoring: increasing the likelihood of success (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. For antibiotics, the peak (Cmax; eg, aminoglycosides [AMG], fluorinated quinolones) depends on the MIC of the infecting organism (target at least 10X the MIC), and the trough depends upon the type of antibiotic (time versus concentration dependent); for AMG, Cmin is targeted to avoid toxicity. Monitoring determines the individual patient's therapeutic range. 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. Factors which determine drug disposition (absorption, distribution, metabolism and excretion) are amenable to change. Physiologic, pathologic and pharmacologic factors can profoundly alter the disposition of a drug such that therapeutic failure or adverse reactions occur. 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. 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.
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. As such, 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. Species differences vary in the production of these metabolites. An effective therapeutic range must have been identified for the drug in the species and for the disease being treated. 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.