TDM: basic pharmacokinetics for dosage adjustments (Proceedings)
Therapeutic drug monitoring (TDM) provides insight on the internal exposure of drug available to reach the site of action. Since therapeutic success for most drugs depends on achieving plasma concentrations (Cp) known to be safe and efficacious, TDM helps minimize the time that elapses before corrective measures can be implemented. Knowledge of basic pharmacokinetic (PK) principles can be applied to the interpretation of clinical drug concentration measurements of the individual patient. Drug disposition may be altered by physiological, pathological and/or pharmacological factors. Being able to assess the effect of disease states on PK parameters through TDM is particularly important in properly adjusting dosages for the unhealthy patient.
Not all drugs require TDM. Drugs with serious toxicity coupled with poorly defined or difficult to detect clinical end points, steep dose-response curves for which a small increase in dose may result in a marked increase in desired or undesired response, and drugs recognized has having a narrow therapeutic ratio are good candidates for TDM. Drugs that exhibit complex PK such as marked interindividual PK variability, nonlinear PK that may lead to rapid accumulation of drug to toxic concentrations and drugs that are prone to toxicity/decrease efficacy due to potential drug interactions are also examples of the types of drug for which therapeutic management benefit from the use of TDM. Finally, TDM is also helpful in cases when drug interactions are suspected or when the cost justifies confirmation of effective Cp in order to minimize dose and duration of therapy with an expensive drug.
For drugs for which TDM is available, a therapeutic range of Cp is clinically established in human patients in order to achieve the desired effect while avoiding toxicity. These therapeutic ranges are generally "borrowed" for the interpretation of Cp measurements in veterinary patients. It is important to keep in mind however that most of these therapeutic ranges have not yet been confirmed in cats and dogs, and that dosage regimens should be tailored to the individual patient.Objectives
1. Provide the practitioner with a list of situations and drugs for which TDM is recommended and available.
2. Provide the practitioner with an understanding of how some physiological, pathological and pharmacological factors may affect drug disposition and how TDM can be helpful.
3. Provide the practitioner with simple pharmacokinetic tools to make individualized dosage adjustments for their patients, according to TDM results.
4. Provide the practitioner with simple tools to make pro-active changes in the dosage regimen for drugs with long half-lives, according to TDM results.
Important factors required for TDM
1. Patient response must correlate with Cp of drug.
2. An effective therapeutic range must be identified for the drug, in the species and the disease for which it is intended to treat, keeping in mind that in general therapeutic ranges established for cats and dogs are extrapolated from human studies and have not been confirmed in these species.
3. Analytical methods must be available to rapidly and accurately detect the Cp in the blood of the particular species being tested.
4. Finally, TDM must be available at a reasonable cost.
Situations for which TDM is useful
1. To identify owner non compliance as a cause of therapeutic failure or toxicity.
2. When an expected therapeutic effect has not been observed.
3. When a high Cp is suspected to be the cause of drug toxicity.
4. To establish therapeutic Cp when dose response is difficult to detect.
5. When a trial and error adjustment in dose is considered unacceptable in cases of life-threatening diseases.
6. When chronic administration is anticipated to establish baseline Cp and monitor PK changes overtime.
Drugs for which TDM is available
1. Anticonvulsants (PB, primidone, KBr, selected benzodiazepines, zonisamide)
2. Aminoglycosides (gentamicin, amikacin)
3. Cardiac drugs (digoxin, procainamide, lidocaine, quinidine)
4. Respiratory drug (theophylline)
5. Immunomodulating drug (cyclosporine)
6. Endocrine drug (levothyroxine)