Therapeutic drug monitoring

Did You Know?

• A priori TDM determines the initial dose regimen based on clinical endpoints and established population pharmacokinetic–pharmacodynamic relationships, using demographic, clinical, and pharmacogenetic data.
• Integrating improved pharmacometrics with model-informed precision dosing can further refine TDM to provide more precisely personalized treatments.
• Data from these approaches can be integrated into the electronic patient record as clinical decision support systems.

Characteristics of drugs candidate to therapeutic drug monitoring

Many medications are used without blood level monitoring because their dosage can be adjusted according to clinical response. For certain drugs, however, insufficient levels lead to undertreatment or resistance, while excessive levels cause toxicity and tissue damage. Indications favoring therapeutic drug monitoring include consistent pharmacodynamic relationships between plasma concentrations and efficacy or toxicity, significant between-patient pharmacokinetic variability, a narrow therapeutic window, inability to optimize dosage by clinical observation alone, treatment duration and criticality justifying adjustment efforts, and potential compliance problems that monitoring might remedy.

TDM determinations are also used to detect and diagnose poisoning. Examples of widely monitored drugs include aminoglycoside antibiotics (gentamicin), antiepileptics (carbamazepine, phenytoin, valproic acid), mood stabilizers (lithium citrate), antipsychotics (pimozide, clozapine), digoxin, ciclosporin, tacrolimus, and increasingly many antibiotics, tyrosine kinase inhibitors, TNF inhibitors, antifungal agents, antiretroviral agents, and psychiatric drugs.

Practice of therapeutic drug monitoring

Automated analytical methods such as enzyme multiplied immunoassay technique and fluorescence polarization immunoassay are widely available for frequently measured drugs. Most other drugs can now be measured using versatile methods like liquid chromatography–mass spectrometry or gas chromatography–mass spectrometry, which have progressively replaced high-performance liquid chromatography. TDM is not limited to providing precise concentration measurements; it also involves appropriate medical interpretation based on robust scientific knowledge.

To guarantee quality of interpretation, the sample must be taken under good conditions: preferably at a stable dosage, at a standardized sampling time (often at the end of a dosing interval), excluding bias from contamination, dilution, or analytical interferences, and with careful recording of sampling time, last dose intake time, current dosage, and influential patient characteristics. Interpretation proceeds through stages: first, determining whether the observed concentration is in the normal range expected under the dosage, considering patient characteristics and population pharmacokinetic studies; second, determining whether the concentration profile is close to the exposure target associated with the best trade-off between therapeutic success probability and toxicity risk, based on clinical pharmacodynamic knowledge of dose-concentration-response relationships.

For example, a result around the 25th percentile suggests high drug clearance; a concentration curve below the acceptance range raises concerns about efficacy; and a doubled dose might be recommended to reach target, assuming good adherence and accurate measurement.