Therapeutic Drug Monitoring of Racemic Venlafaxine and Its Main Metabolites in an Everyday Clinical Setting

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Abstract
When Efexor® (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n = 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.