Analytical aspects of TDM of psychoactive drugs

Therapeutic drug monitoring (TDM) is an established means to improve safety and efficacy of treatment with psychoactive drugs. The plasma level is used as a surrogate marker for availability of the drug at its targets with the numerical result taken for granted. However, several aspects of the preanalytical and analytical phase contribute to the total error of measurement and deserve consideration.

Drugs may be light sensitive and concentrations can decrease ex vivo whenever blood is not drawn in a light protected container (e.g. chlorprothixene, promethazine). A steady-state sample drawn before taking the next dose (trough level) is appropriate for most drugs. However, drugs with short half-life taken at bedtime (agomelatine) can only be monitored for compliance when metabolites of longer half-life are also measured. Clinical laboratories often report metabolite concentrations and metabolic ratios (MR =[metabolite]: [parent drug]). A MR outside the reference range can indicate non steady-state conditions or altered drug metabolism by CYP P450 enzymes due to inhibition, induction or genetic polymorphism.

Most psychoactive drugs will be monitored using in-house developed tests. These methods must be validated according to accepted standards (DAKKS, FDA, CLIA). Accuracy, precision, analytic sensitivity and analytic specificity must be proven until a method is finally accepted as valid. Provision of TDM for new drugs or drugs with a low market share may be difficult because of unavailable reference substances for the drug or its metabolites and uncertain purity and stability of these substances.

A better understanding of these sources of measurement variability may improve the utilization of TDM test results.