Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed. TDM aimed at improving patient care by individually adjusting the dose of drugs for which clinical experience or clinical trials have shown it improved outcome in the general or special populations. It can be based on a a priori pharmacogenetic, demographic and clinical information, and/or on the a posteriori measurement of blood concentrations of drugs or biological surrogate or end-point markers of effect. There are numerous variables that influence the interpretation of drug concentration data: time, route and dose of drug given, time of blood sampling, handling and storage conditions, precision and accuracy of the analytical method, validity of pharmacokinetic models and assumptions, co-medications and, last but not least, clinical status of the patient. Many different professionals are involved with the various elements of drug concentration monitoring, which is a truly multidisciplinary process. Because failure to properly carry out any one of the components can severely affect the usefulness of using drug concentrations to optimize therapy, an organized approach to the overall process is critical.
''A priori'' therapeutic drug monitoring
A priori TDM consists of determining the initial dose regimen to be given to a patient, based on clinical endpoint and on established population pharmacokinetic-pharmacodynamic relationships. These relationships help to identify sub-populations of patients with different dosage requirements, by utilizing demographic data, clinical findings, clinical chemistry results, and/or, when appropriate, pharmacogenetic characteristics.
''A posteriori'' therapeutic drug monitoring
The concept of a posteriori TDM corresponds to the usual meaning of TDM in medical practice, which refers to the readjustment of the dosage of a given treatment in response to the measurement of an appropriate marker of drug exposure or effect. TDM encompasses all aspects of this feedback control, namely:
it includes pre-analytical, analytical and post-analytical phases, each with the same importance;
it is most often based on the specific, accurate, precise and timely determinations of the active and.or toxic forms of drugs in biological samples collected at the appropriate times in the correct containers, or can employ the measurement of a biological perimeter as a surrogate or end-point marker of effect e.g. concentration of an endrogenous compound, enzymatic activity, gene expression, etc. either as a complement to PK monitoring or as the main TDM tool;
it requires interpretation of the results, taking into account pre-analytical conditions, clinical information and the clinical efficiency of the current dosage regimen; this can be achieved by the application of PK-PD modeling;
it can potentially benefit from population PK/PD models possibly combined with individual pharmacokinetic forecasting techniques, or pharmacogenetic data.
Characteristics of drugs candidate to therapeutic drug monitoring
In pharmacotherapy, many medications are used without monitoring of blood levels, as their dosage can generally be varied according to the clinical response that a patient gets to that substance. For certain drugs, this is impracticable, while insufficient levels will lead to undertreatment or resistance, and excessive levels can lead to toxicity and tissue damage. Indications in favor of therapeutic drug monitoring include:
consistent, clinically established pharmacodynamic relationships between plasma drug concentrations and pharmacological efficacy and/or toxicity;
significant between-patient pharmacokinetic variability, making a standard dosage achieve different concentration levels among patients ;
narrow therapeutic window of the drug, which forbids giving high doses in all patients to ensure overall efficacy;
drug dosage optimization not achievable based on clinical observation alone;
duration of the treatment and criticality for patient's condition justifying dosage adjustment efforts;
potential patient compliance problems that might be remedied through concentration monitoring.
TDM determinations are also used to detect and diagnose poisoning with drugs, should the suspicion arise. Examples of drugs widely analysed for therapeutic drug monitoring:
Determine whether the observed concentration is in the “normal range” expected under the dosage administered, taking into account the patient's individual characteristics. This requires referring to population pharmacokinetic studies of the drug in consideration.
Determine whether the patient's concentration profile is close to the “exposure target” associated with the best trade-off between probability of therapeutic success and risk of toxicity. This refers to clinical pharmacodynamic knowledge describing dose-concentration-response relatinships among treated patients.
If the observed concentration is plausible but far from the suitable level, determine how to adjust the dosage to drive the concentration curve close to target. Several approaches exist for this, from the easiest “rule of three” to sophisticated computer-assisted calculations implementing Bayesian inference algorithms based on population pharmacokinetics.
Ideally, the usefulness of a TDM strategy should be confirmed through an evidence-based approach involving the performance of well-designed controlled clinical trials. In practice however, TDM has undergone formal clinical evaluation only for a limited number of drugs to date, and much of its development rests on empirical foundations. Point-of-care tests for an easy performance of TDM at the medical practice are under elaboration.
