Clinical Pharmacokinetics of Mirtazapine

Abstract

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

Étude du comportement analytique de la mirtazapine en chromatographie liquide haute performance et électrophorèse capillaire de zone

“…Les concentrations plasmatiques sont dose-dépendantes avec un pic plasmatique (30 ng/mL -200 ng/mL) atteint au bout de 2 h et une demi-vie plasmatique comprise généralement entre 20 et 40 h (8,15). Elle subit une déméthylation hépatique (cytochrome P450 3A), une hydroxylation (cytochrome P450 2D6 et 1A2) et une glucurocongugaison, à l'origine de nombreux metabolites dont la majorité est inactive.…”

“…Seul le dérivé déméthylé, la déméthylmirtazapine, s'avère actif mais il est présent dans le plasma en concentration très faible. Approximativement 75 % de la dose ingérée est élimi-née dans les urines (2,8,15).…”

Development and Validation of an LC-MS/MS Method for Quantitative Analysis of Mirtazapine in Human Plasma

“…It is rapidly and well absorbed after oral administration, and is and is extensively metabolized by hepatic cytochrome P450 enzymes (CYP). Its elimination halflife ranges between 20 and 40 h and N-desmethy-lmirtazapine is the only pharmacologically active metabolite [3][4][5]. MTZ is administered in a single daily dose, which range between 15 and 45 mg/day, resulting in plasma concentrations between 5 and 100 ng·mL -1 [2].…”

Análise enantiosseletiva da mirtazapina em plasma: comparação de métodos de preparação das amostras

“…Desde então ela tem sido aprovada para uso diário como antidepressivo em um número cada vez maior de outros países (Fawcett;Barkin, 1998) A mirtazapina é um fármaco de caracter básico e lipofílico que, quando administrada por via oral, é rapidamente absorvida; apresenta biodisponibilidade de 50% e a concentração plasmática máxima é alcançada em 2 horas. A meia-vida de eliminação da mirtazapina é 20-40 horas e ela é razoavelmente ligada às proteínas plasmáticas, com concentrações livres ≤15% (Timmer; Sitsen; Delbressine, 2000). A sua disposição cinética depende do sexo e da idade: mulheres e idosos apresentam concentrações plasmáticas maiores que homens e jovens adultos (Cohen et al, 1997;Sitsen;Delbressine, 2000;Gareri et al, 2000).…”

“…A sua disposição cinética depende do sexo e da idade: mulheres e idosos apresentam concentrações plasmáticas maiores que homens e jovens adultos (Cohen et al, 1997;Sitsen;Delbressine, 2000;Gareri et al, 2000). -Glicuronida (aproximadamente 25%) (Delbressine et al, 1998;Sitsen;Delbressine, 2000).…”