Individual and Dose-Dependent Variability in R- and S-Mirtazapine Ratio Among Patients Treated with Racemic Mirtazapine

Aim: Mirtazapine (MIR) is a racemate of the two enantiomers R- and S-MIR. R- and S-MIR are metabolized by different CYP450 isoenzymes. The aim of this study was to investigate whether the R-/S-MIR ratio differs significantly between individuals using the same dose of racemic MIR, and whether observed variation in ratio could be dose-dependent.

Method: A method of enantiomeric separation using a chiral column (Chirobiotic V™) on a Micromass LC-MS/MS instrument was developed and validated. R- and S-MIR were determined in serum samples from 91 patients receiving racemic MIR as part of their clinical treatment. The patients were divided into groups according to dosage. Statistical analyses were performed using student t-test, Mann Whitney-test and Spearman correlation coefficients.

Results: Increased dosage resulted in significantly increased serum levels of R- and S-MIR as well as racemic MIR. Mean levels of R-MIR were significantly higher than S-MIR at all dose levels and correlated more closely to mean levels of racemic MIR. There was a substantial inter-individual variance in R-/S-MIR ratio among patients using the same dose. The R-/S-MIR ratio varied between 0.5 and 7.0 among the individuals and was not significantly influenced by gender. The mean ratio, however, varied only between 2.0 and 3.4. The mean R-/S-MIR ratio increased at doses from 15mg to 45mg daily. Higher doses decreased the ratio.

Conclusions: Due to enantioselective pharmacokinetics and the substantial inter-individual variance, separate quantification of the enantiomers may be important in evaluating clinical response in the individual patient.