Therapeutic drug monitoring
Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed. TDM aims 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 priori pharmacogenetic, demographic and clinical information, and/or on the a posteriori measurement of blood concentrations of drugs (pharmacokinetic monitoring) or biological surrogate or end-point markers of effect (pharmacodynamic monitoring).
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 clinical status of the patient (i.e. disease, renal/hepatic status, biologic tolerance to drug therapy, etc.).
Many different professionals (physicians, clinical pharmacologists, clinical pharmacists, nurses, medical laboratory scientists, etc.) 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 (PK/PD) 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.— IATDMCT Executive Committee, Definition of TDM
A posteriori therapeutic drug monitoring
- includes pre-analytical, analytical and post-analytical phases, each with the same importance;
- 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 (PK monitoring), or can employ the measurement of a biological perimeter as a surrogate or end-point marker of effect (PD monitoring) 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;
- 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;
- can potentially benefit from population PK/PD models possibly combined with individual pharmacokinetic forecasting techniques, or pharmacogenetic data.— IATDMCT Executive Committee, Definition of TDM
Characteristics of drugs subject 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. In a small group of drugs, this is impossible, as insufficient levels will lead to undertreatment or resistance, and excessive levels can lead to toxicity and tissue damage.
Indications for therapeutic drug monitoring include:
- There is an experimentally determined relationship between plasma drug concentration and the pharmacological effect.
- Knowledge of the drug level influences management.
- There is a narrow therapeutic window
- There are potential patient compliance problems.
- The drug dose cannot be optimised by clinical observation alone.
Examples of drugs analysed by therapeutic drug monitoring:
- Aminoglycoside antibiotics (gentamicin)
- Antiepileptics (such as carbamazepine, phenytoin and valproic acid)
- Mood stabilisers, especially lithium citrate
- Antipsychotics (such as pimozide and clozapine)
- Biologic monoclonal antibody drugs (such as adalimumab, certolizumab pegol and infliximab)
Therapeutic drug monitoring can also detect poisoning with above drugs, should the suspicion arise.
- Marshall WJ, Bangert SK. Clinical Chemistry, 6th Edition. Edinburgh, London: Mosby Elsevier. 2008. ISBN 978-0-7234-3455-9
- IATDMCT Executive Committee. "Definition of TDM", 2004, accessed July 18, 2011.
- Burton ME, Shaw LM, Schentag JJ, Evans, WE. Applied Pharmacokinetics & Pharmacodynamics, 4th Edition. Baltimore, Philadelphia: Lippincott Williams & Wilkins. 2006. ISBN 978-0-7817-4431-7