Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism

Background: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. Methods: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V-0 (n = 905), a group of patients co-medicated with doxepin, V-DOX (n = 25) and a second group, co-medicated with mirtazapine, V-MIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. Results: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p<0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p<0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p<0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. Conclusions: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. Limitations: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording

Sex and body weight are major determinants of venlafaxine pharmacokinetics

We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and dose-corrected plasma concentrations (C/D). A database containing concentrations of VEN and ODVEN including 737 of 1594 eligible patients was analyzed. Analyses included sex, body weight, and BMI as well as concentrations of VEN, ODVEN, AM, and C/D. A positive correlation was detected between body weight and daily dosage (r(s)=0.168, P<0.001). A negative correlation was found between body weight and AM (r(s)=-0.124, P=0.001) and ODVEN (r(s)=-0.137, P<0.001). Negative correlations were also found between body weight and C/D ratios (C/D VEN: r(s)=-0.134, P<0.001, C/D ODVEN: r(s)=-0.239, P<0.001, C/D AM: r(s)=-0.256, P<0.001). No correlations were detected between BMI and concentrations for VEN, ODVEN, and AM. Comparing low-BMI (<20kg/m(2)), medium-BMI (20-29.9kg/m(2)), and high-BMI (30kg/m(2)) groups, higher values of some pharmacokinetic variables in the lower BMI group did not remain significant after controlling for sex. Women had higher VEN, ODVEN, AM, and C/D values for AM, VEN, and ODVEN than men (P<0.001 for all comparisons). Our results highlight the role of different pharmacokinetically relevant parameters and foremost of sex as mediators for the effect of BMI on VEN metabolism

Standards zur Qualitaetssicherung in der Markt- und Sozialforschung

Die Verfasser legen einen den gesamten Forschungsprozess umfassenden Orientierungsrahmen vor, der Standards zur Qualitaetssicherung setzen und darueberhinaus eine Grundlage fuer die Zertifizierung von Markt- und Sozialforschungsinstituten nach ISO 9000 bilden soll. Neben allgemeinen Aspekten der Qualitaetssicherung wie Qualitaetsmanagement, Mitarbeiterschulung und Vertraulichkeit werden die Gestaltung der Zusammenarbeit mit dem Auftraggeber, die konzeptionelle Studienbegleitung, die Datenerhebung und Datenverarbeitung sowie die Beratung des Auftraggebers beruecksichtigt. Der gesamte Text liegt zweisprachig in deutsch und englisch vor. (ICE)SIGLEAvailable from UuStB Koeln(38)-20000106016 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman