Pharmacokinetics and safety of mirtazapine in caucasian and japanese young healthy male volunteers

Abstract

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). In a double-blind, placebo controlled, parallel design multiple dose study, the pharmacokinetics and safety of multiple daily doses of mirtazapine and placebo have been compared in healthy Japanese and Caucasian male volunteers. All subjects received once daily in the evening an oral dose of mirtazapine or placebo over a period of 27 consecutive days. In order to achieve steady-state at every daily dose level, 15 mg mirtazapine or placebo was administered for the first 9 days, followed by 30 mg or placebo for a further 9 days and 45 mg or placebo for the final 9 days. Trough plasma concentrations of mirtazapine and Org 3838 (its demethyl metabolite) were measured while 24 hour plasma profiles were determined after dosing on days 9, 18 and 27; additional samples were collected up to 120 hours after the last 45 mg dose. Eleven Japanese (two on placebo) and 15 Caucasian (two on placebo) subjects completed this study, except for one Caucasian subject (treated with mirtazapine), who dropped out on day 20 for reasons unrelated to the study. The administration of mirtazapine over 27 days in 9 day periods of increasing doses (15 mg, 30 mg and 45 mg) was well tolerated by both Japanese and Caucasian subjects; fatigue was the most frequently reported AE. Liver enzyme increases (particularly ASAT and ALAT) were observed in some subjects in both ethnic groups. In all cases, these increases decreased during the course of the study despite the continued use of increasing doses of mirtazapine. The average plasma concentration of mirtazapine in Japanese subjects was 41% higher than that in Caucasian subjects. After correction for body weight this difference was reduced to 22%. The mean plasma concentrations of Org 3838 in Japanese and in Caucasian subjects were approximately the same. The observed difference of mirtazapine plasma concentrations is considered to be of no practical clinical relevance. Clinical Pharmacology & Therapeutics (2004) 75, P36–P36; doi: 10.1016/j.clpt.2003.11.138