PS213. Pharmacokinetics of mirtazapine and its hydroxylated metabolite in Japanese psychiatric patients treated with mirtazapine

Objectives: Venlafaxine is metabolized by CYP2D6 to O-desmethylvenlafaxine (ODV) and by CYP3A4 to N-desmethylvenlafaxine (NDV). CYP2C19 is also involved in the formation of ODV. The PPIs omeprazole and pantoprazole inhibit CYP2C19 to a different extent. Aim of this study was to investigate the potential effects of both PPIs on serum levels of VEN and ODV. Methods: From a therapeutic drug monitoring (TDM) database, serum concentrations of VEN, ODV and the active moiety (VEN + ODV), were analyzed. Data from 120 patients were available and splitted into three groups: patients without PPI [noPPI], with pantoprazole [PANTO] or with omeprazole [OMEP] (n=40 each). The ratio of (ODV/VEN) was calculated as a marker of the metabolizer status. Results: Median test detected no differences regarding the median daily dosage of VEN between the three groups (p=0.995); the mean daily doses for VEN were 207.6mg/d, SD=79.96 in the control-group, 209.06mg/d, SD=78.24 for the pantoprazole group and 203.43mg/d, SD=91.41 for omeprazole group. Plasma concentrations for VEN + ODVEN in the PANTO group were significantly higher than in the control group (p=0.019 for Mann-Whitney U Test). Plasma concentrations for ODVEN and VEN + ODVEN in the OMEP group were significantly higher than in the control group (p=0.001 and p=0.017 for Mann-Whitney U Test) Conclusion: Both, omeprazole and pantoprazole led to a varying extent in increases of the serum concentrations of the active moiety (sum of VEN+ODV). The increase is driven by significantly higher levels of ODV in the OMEP group. This might be due to distinct CYP2C19 blocking properties of both PPIs, hindering the 2C19 mediated metabolization of VEN to N-desmethylvenlafaxine (NDV). PS213 Pharmacokinetics of mirtazapine and its hydroxylated metabolite in Japanese psychiatric patients treated with mirtazapine Takashi Watanabe1, Kazufumi Akiyama1, Akiko Aoki1, Yuki Hayashi1, Yoshimasa Inoue1, Shin Ishiguro1, Kazuko Kato2, Jason Pierce1, Kazutaka Shimoda1, Masataka Shinozaki1, Shoko Tsuchimine3, Mikito Ueda1, Norio Yasui-Furukori3 1Dokkyo Medical University, Japan, 2Sakura La Mental Clinic, Japan, 3Hirosaki University, Japan Abstract Purpose: This study investigated the pharmacokinetics of mirtazapine (MIR) and its hydroxylated metabolite in Japanese psychiatric patients. Patients and Methods: The subjects were 59 Japanese patients treated with racemic MIR. The steady-state plasma concentrations of MIR and N-desmethylmirtazapine (DMIR), 8-hydroxyMIR (8-OH-MIR) were measured using high performance liquid chromatography. CYP2D6 genotypes were determined by polymerase chain reaction. Three subjects whose plasma levels of MIR and DMIR were below the limit of detection were regarded as non-adherent and excluded. Multiple regression analysis (stepwise method) was performed to analyze the relationship between subject-independent variables (gender, age, smoking status and number of mutated CYP2D6 alleles) and subjectdependent variables such as plasma concentrations of MIR, DMIR, 8-OH-MIR (ng/ml/mg/kg; all corrected for dose and body weight) and 8-OH-MIR/MIR ratio. Results: Multiple regression analysis revealed that smoking (p=0.016) and gender (p=0.041) had a significant impact on plasma concentrations of MIR. The final models were described by the following equations: Plasma concentration of MIR = 86.6 31.9 ×smoking status (smoking=1, non-smoking=0) 23.0 × gender (male=1, female=0) (R= 0.45, p=0.002, coefficient of determination (R2) =0.20). Smoking status was a significant factor correlated to plasma concentration of 8-OH-MIR (p=0.034). The final model was described by the following equation: Plasma concentration of 8-OH-MIR (corrected for dose and body weight) = 2.41 1.59×smoking status (smoking=1, non-smoking=0) (R= 0.29, p=0.034, R2=0.08). There were no significant factors correlated to in 8-OH-MIR/MIR ratio in the multiple regression analysis. Conclusion: Gender and smoking polymorphism might affect pharmacokinetics of racemic MIR in Japanese patients.Purpose: This study investigated the pharmacokinetics of mirtazapine (MIR) and its hydroxylated metabolite in Japanese psychiatric patients. Patients and Methods: The subjects were 59 Japanese patients treated with racemic MIR. The steady-state plasma concentrations of MIR and N-desmethylmirtazapine (DMIR), 8-hydroxyMIR (8-OH-MIR) were measured using high performance liquid chromatography. CYP2D6 genotypes were determined by polymerase chain reaction. Three subjects whose plasma levels of MIR and DMIR were below the limit of detection were regarded as non-adherent and excluded. Multiple regression analysis (stepwise method) was performed to analyze the relationship between subject-independent variables (gender, age, smoking status and number of mutated CYP2D6 alleles) and subjectdependent variables such as plasma concentrations of MIR, DMIR, 8-OH-MIR (ng/ml/mg/kg; all corrected for dose and body weight) and 8-OH-MIR/MIR ratio. Results: Multiple regression analysis revealed that smoking (p=0.016) and gender (p=0.041) had a significant impact on plasma concentrations of MIR. The final models were described by the following equations: Plasma concentration of MIR = 86.6 31.9 ×smoking status (smoking=1, non-smoking=0) 23.0 × gender (male=1, female=0) (R= 0.45, p=0.002, coefficient of determination (R2) =0.20). Smoking status was a significant factor correlated to plasma concentration of 8-OH-MIR (p=0.034). The final model was described by the following equation: Plasma concentration of 8-OH-MIR (corrected for dose and body weight) = 2.41 1.59×smoking status (smoking=1, non-smoking=0) (R= 0.29, p=0.034, R2=0.08). There were no significant factors correlated to in 8-OH-MIR/MIR ratio in the multiple regression analysis. Conclusion: Gender and smoking polymorphism might affect pharmacokinetics of racemic MIR in Japanese patients. PS214 Cerebral and peripheral Tryptophan / kynurenine pathway in the pathophysiology of stress-induced bio-behavioural abnormalities