Population pharmacokinetic analysis of mirtazapine.
OBJECTIVE
Mirtazapine belongs to the new generation of antidepressants that is commonly used in clinical routine. Therefore, we feel it mandatory to control compliance in the context of non-response, adverse events or other clinical situations by means of plasma concentration measurements. While controlled clinical studies have evaluated the effect of individual covariates on the pharmacokinetics of mirtazapine, our analysis aims to identify covariates within a naturalistic clinical setting.


METHODS
We performed non-linear mixed-effects modelling with data from 65 depressed inpatients whose plasma concentrations were measured weekly during their stay in hospital. Each patient's age, height, weight, co-medication, alcohol, coffee and cigarette consumption, weekly serum creatinine concentrations, liver enzyme activity, blood pressure and pulse was noted. From 49 patients, the genotype of cytochrome P450 (CYP) isoenzymes 2D6, 2C9 and 2C19 was analysed.


RESULTS
The clearance of CYP2D6 intermediate metabolisers was reduced by 26% compared with extensive metabolisers. No other factor significantly influenced the clearance of these patients.


CONCLUSIONS
The variability of mirtazapine plasma concentrations in clinical routine is caused to a relevant degree by CYP2D6. This should be taken into account when therapeutic drug monitoring is carried out to check treatment adherence or when a special clinical situation, such as co-morbidity and add-on medication, demands careful dosing of this drug.
Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53121 Bonn, Germany.
Katja
K
Grasmäder
Petra Louise
PL
Verwohlt
Kai-Uwe
KU
Kühn
Aleksandra
A
Dragicevic
Olrik
O
von Widdern
Astrid
A
Zobel
Christoph
C
Hiemke
Marcella
M
Rietschel
Wolfgang
W
Maier
Ulrich
U
Jaehde
Marie Luise
ML
Rao
D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008803:Mianserin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D000078785:Mirtazapine
D000929:Antidepressive Agents, Tricyclic; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D008803:Mianserin; D000078785:Mirtazapine; D019389:Cytochrome P-450 CYP2D6