Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

Abstract

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.

The prevalence of off-label use and supratherapeutic blood levels of outpatient psychotropic medication in suicidal adolescents

“…Tolerability decreases above that upper limit ( 12 ). Therapeutic improvement is less likely ( 20 , 27 ). Clear recommendations on how to treat adjustment disorders are missing; moreover, knowledge of pharmacological treatment is very limited ( 38 ).…”

“…Given that an antidepressant drug at a therapeutic level reduces depressive symptoms better than an antidepressant agent at a subtherapeutic (i.e., low therapeutic response) or supratherapeutic level, there is much potential for improvement as five of our depressed adolescent cases showed subtherapeutic levels of fluoxetine and six cases had supratherapeutic levels ( 27 ). Sertraline serum levels were mostly in the therapeutic range as well.…”

“…In case of continuing the prescribed psychotropic medication, dose adjustments should be made in the hospital, using TDM. Whenever possible, deprescribing to reduce polypharmacy and to react to supratherapeutic levels of (off-label) medication should be an important part of hospital care ( 27 ). In the case of depressed adolescents with prescribed antidepressant medication and subtherapeutic levels, after anamnesis, proof of adherence, and dosage check, we recommend an increase of dosage and serum level control after 7 days (TDM).…”

“…We examined if serum levels of new-generation antidepressants and antipsychotics approved in Germany for adolescents or in clinical studies tested and frequently prescribed were in the therapeutic range (12)(13)(14)(15)(24)(25)(26)(27). We used the following therapeutic reference ranges: aripiprazole 100-350 ng/mL, quetiapine: 100-500 ng/mL, risperidone (i.e., risperidone plus 9-hydroxy-risperidone): 20-60 ng/mL, fluoxetine (i.e., fluoxetine plus N-Desmethylfluoxetine): 120-500 ng/ mL; mirtazapine: 30-80 ng/L, sertraline: 10-150 ng/mL, pipamperone: 56.0-180.5 ng/mL (23,27). In Germany, pipamperone is indicated for sleeping disorders and psychomotor agitation (i.e., symptoms and behavioral problems, no diagnoses).…”