Clinical Pharmacokinetics

, Volume 38, Issue 6, pp 461–474 | Cite as

Clinical Pharmacokinetics of Mirtazapine

  • Cees J. TimmerEmail author
  • J. M. Ad Sitsen
  • Leon P. Delbressine
Review Article


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±3.1h). 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 μg/L.


Fluoxetine Risperidone Cimetidine Paroxetine Amitriptyline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    De Boer T, Nefkens F, van Helvoirt A. The α2-antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol. 1994; 253: R5–6.CrossRefGoogle Scholar
  2. 2.
    De Boer T, Ruigt GSR. The selective α2-adrenoreceptor antagonist Org 3770 (mirtazapine) enhances noradrenergic and serotonin1a-mediated serotonergic neurotransmission. CNS Drugs. 1995; 4 Suppl. 1: 29–38.CrossRefGoogle Scholar
  3. 3.
    De Montigny C, Haddjeri N, Mongeau R, et al. The effects of mirtazapine on interactions between central noradrenergic and serotonergic systems. CNS Drugs. 1995; 4 Suppl. 1: 13–17.CrossRefGoogle Scholar
  4. 4.
    Bremner JD. A double-blind comparison of Org 3770, amitriptyline and placebo in major depression. J Clin Psychiatry. 1995; 56: 519–25.PubMedGoogle Scholar
  5. 5.
    Claghorn JL, Lessem MD. A double-blind placebo controlled study of Org 3770 in depressed outpatients. J Affective Disorders. 1995; 34: 165–71.CrossRefGoogle Scholar
  6. 6.
    Sitsen JMA, Zivkov M, Dieterle D. Wirksamkeit under Verträglichkeit von Org 3770 bei Patienten mit einer Major Depression. Psychopharmakotherapie. 1995; 2: 68–71.Google Scholar
  7. 7.
    Van Moffaert M, De Wilde J, Vereecken A, et al. Mirtazapine is more effective than trazodone: a controlled study in hospitalised patients with major depression. Int Clin Psychopharmacol. 1995; 10: 3–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Wheatley DP, van Moffaert M, Timmerman L, et al. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. Mirtazapine-Fluoxetine Study Group. J Clin Psychiatr. 1998; 59: 306–12.Google Scholar
  9. 9.
    Zivkov M, De Jongh G. Org 3770 vs amitriptyline: a 6-week randomised double-blind multicentre trial in hospitalised patients. Hum Psychopharmacol. 1995; 10: 263–71.CrossRefGoogle Scholar
  10. 10.
    Mullin J, Lodge A, Bennie E, et al. Amulticentre double-blind, amitriptyline-controlled study of mirtazapine in patients with major depression. J Psychopharmacol. 1996; 10: 235–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Richou H, Ruimy P, Charbaut J, et al. A multicentre, double-blind, clomipramine-controlled efficacy and safety study of Org 3770. Hum Psychopharmacol. 1995; 10: 263–71.CrossRefGoogle Scholar
  12. 12.
    Marttilla M, Jääskeläinen J, Järvi R, et al. A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharmacol. 1995; 5: 441–6.Google Scholar
  13. 13.
    Montgomery SA. Clinically relevant sizes in depression. Eur Neuropsychopharmacol. 1994; 4: 283–4.CrossRefGoogle Scholar
  14. 14.
    Leinonen E, Skarstein J, Behnke K, et al. Efficacy and tolerability of mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive disorder. Int Clin Psychopharmacol. 1999; 14: 329–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Thompson C. Mirtazapine versus selective serotonin reuptake inhibitors. J Clin Psychiatry. 1999; 60 Suppl. 17: 18–22.PubMedGoogle Scholar
  16. 16.
    Montgomery SA. New developments in the treatment of depression. J Clin Psychiatry. 1999; 60 Suppl. 14: 19–5.Google Scholar
  17. 17.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Association, 1980.Google Scholar
  18. 18.
    Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo controlled trial in depressed elderly patients. Hum Psychopharmacol. 1995; 10 Suppl. 2: S125–33.CrossRefGoogle Scholar
  19. 19.
    Hoeyberg OJ, Maragakis B, Mullin J, et al. A double blind multicentre comparison of mirtazapine and amitriptyline in elderly depressed patients. Acta Psychiatr Scand. 1996; 93: 184–90.CrossRefGoogle Scholar
  20. 20.
    Cohen M, Panagides J, Timmer CJ, et al. Pharmacokinetics of mirtazapine from orally administered tablets: influence of a high-fat meal. Eur J Drug Metab Pharmacokinet. 1997; 22: 103–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Colbers EPH, Boom SPA, Kleijn HJ, et al. Single-dose, fasting, open, randomized, two-way cross-over bioequivalence study on Org 3770 oral liquid versus 15 mg tablet in thirty-two healthy volunteer subjects [Study 22523, Report No. NL 0012550]. Oss: N.V. Organon, 1999. (Data on file).Google Scholar
  22. 22.
    Voortman G, Paanakker JE. B ioavailability of mirtazapine from Remeron® tablets after single and multiple oral dosing. Hum Psychopharmacol 1995; 10 Suppl.: S83–96.CrossRefGoogle Scholar
  23. 23.
    Bengtsson F, Höglund P, Timmer C, et al. Mirtazapine oral single dose kinetics in patients with different degrees of renal failure. Hum Psychopharmacol. 1998; 13: 357–65.CrossRefGoogle Scholar
  24. 24.
    Murdoch DL, Ashgar J, Ankier SI, et al. Influence of hepatic impairment on the pharmacokinetics of single doses of mirtazapine in elderly subjects [abstract]. Br J Clin Pharmacol. 1993; 35: 76P.Google Scholar
  25. 25.
    Timmer CJ, Paanakker JE, van Hal HJM. Pharmacokinetics of mirtazapine from orally administered tablets: influence of gender, age and treatment regimen. Hum Psychopharmacol. 1996; 11: 497–509.CrossRefGoogle Scholar
  26. 26.
    Paanakker JE, Tjepkema S, Timmer CJ. Pharmacokinetics of Org 3770 in young healthy male volunteers after a single oral administration of 30 and 45 mg: dose linearity testing [Study 86020, Report No. 2167]. Oss: N.V. Organon, 1988. (Data on file).Google Scholar
  27. 27.
    Timmer CJ, Paanakker JE, Mink CPA, et al. Assessment of the bioequivalence of four oral Org 3770 formulations (30mg tablet, 15mg tablet, 5mg tablet and 5mg capsule) in healthy, young, male subjects [Study 88003, Report No. 2499]. Oss: N.V. Organon, 1989. (Data on file).Google Scholar
  28. 28.
    Sitsen JMA, Voortman G, Timmer C. Pharmacokinetics of mirtazapine and lithium in healthy male subject. J Clin Psychopharmacol. In press.Google Scholar
  29. 29.
    Vrijmoed-De Vries MC, Kleijn HJ, Colbers EPH, et al. Single-dose, fasting, open, two-way cross-over bioequivalence trial on Org 3770 30 mg OraSolv® tablet versus 30 mg Org 3770 marketed tablet in 40 healthy subjects [Study 22527, Report No. NL 0016343]. Oss: N.V. Organon, 1999. (Data on file).Google Scholar
  30. 30.
    Timmer CJ, Paanakker JE, Van Hal HJM. Pharmacokinetics of Org 3770 in young healthy male volunteers after sub-chronic oral administration of escalating daily doses (15–80 mg): dose linearity testing [Study 87003, Report No. 2166]. Oss: N.V. Organon, 1988. (Data on file).Google Scholar
  31. 31.
    Timmer CJ, Lohmann AAM, Mink CPA. Pharmacokinetic dose-proportionality study at steady state of mirtazapine from Remeron® tablets. Hum Psychopharmacol 1995; 10 Suppl.: S97–106.CrossRefGoogle Scholar
  32. 32.
    Peeters PAM, Brett MA, Van den Heuvel MW. A phase I, multiple dose, pharmacokinetic and safety comparison study of Org 3770 between healthy male Japanese and Caucasian volunteers [Study 22525]. Oss: N.V. Organon, 2000. (Data on file).Google Scholar
  33. 33.
    Timmer CJ, Paanakker JE, Vrijmoed-De Vries M. Mirtazapine pharmacokinetics with two dosage regimens and two pharmaceutical formulations. Pharm Res. 1997; 14: 98–102.PubMedCrossRefGoogle Scholar
  34. 34.
    Mink L, Heftink N, Jonkman JGH, et al. Pharmacokinetics of mirtazapine in combination with amitriptyline. 11th European College of Neuropsychopharmacology Congress; 1998 Oct 31-Nov 4; Paris, 1.039.Google Scholar
  35. 35.
    Ebes F, Van Lookeren-Campagne AM, Hartmans HLA, et al. A phase I, single center, single-blind, placebo-controlled multiple dose study of the interaction between Org 3770 and carba-mazepine in healthy male volunteers [Study 22514, Report No. NL 0003854]. Oss: N.V. Organon, 1998. (Data on file).Google Scholar
  36. 36.
    Sitsen JMA, Maris FA, Timmer CJ. Concomitant use of mirtazapine and cimetidine: a drug-drug interaction study in healthy male subjects. Eur J Clin Pharmacol. In press.Google Scholar
  37. 37.
    Van Lookeren-Campagne AM, Hartmans HLA, Ruwe FJL, et al. A phase I, single center, randomized, partially double-blind, multiple dose, three-way cross-over study of the pharmacokinetic and pharmacodynamic interaction of Org 3770 (mirtazapine) and paroxetine in healthy volunteers [Study 22511, Report No. NL 0010166]. Oss: N.V. Organon, 1998. (Data on file).Google Scholar
  38. 38.
    Delbressine LPC, Moonen MEG, Kaspersen FM, et al. Pharmacokinetics and biotransformation of mirtazapine in human volunteers. Clin Drug Invest. 1998; 15: 45–55.CrossRefGoogle Scholar
  39. 39.
    Midha K. Biointernational ’89. Int Pharm J 4. 1990; 3: 101–3.Google Scholar
  40. 40.
    Van der Vorstenbosch CG, Delbressine LPC. Binding of Org 3770 to human plasma proteins and human liver proteins [Report No. 2157]. Oss: N.V. Organon, 1988. (Data on file).Google Scholar
  41. 41.
    Vos RME. A pilot study on in vitro binding of Org 3770 to human erythrocytes [Report No. 3384]. Oss: N.V. Organon, 1993. (Data on file).Google Scholar
  42. 42.
    Dahl ML, Voortman G, Alm C, et al. In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest. 1997; 13: 37–46.CrossRefGoogle Scholar
  43. 43.
    Broekkamp CLE, Delbressine LPC, Rijk HW, et al. (+)-Mirtazapine and (+)-desmethylmirtazapine levels in rat brain in relation to in vivo blockade of α2-receptors. Eur Neuropsychopharmacol. 1996; 6 Suppl. 3: 52–3.CrossRefGoogle Scholar
  44. 44.
    De Graaf JS, Delbressine LPC. Contributions of the enantiomers of mirtazapine (Org 3770) and its demethyl metabolite to its neuropharmacological profile in rats. Eur J Pharmacol 1990; 183; 583–4.CrossRefGoogle Scholar
  45. 45.
    Mink CPA, Timmer CJ. A single-centre, double-blind, placebo-controlled phase I study in healthy male volunteers to assess the safety, tolerance and pharmacokinetics of intravenously administered Org 3770 [Study 22505, ReportNo. 3309]. Oss: N.V. Organon, 1993. (Data on file).Google Scholar
  46. 46.
    Simpson GM, Yadalam KG, Levinson DF, et al. Single dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration. J Clin Psychophamacol. 1990; 10: 417–21.CrossRefGoogle Scholar
  47. 47.
    Haring C, Meise U, Humpel C, et al. Dose-related plasma levels of clozapine: influence of smoking behavior, sex and agea. Psychopharmacology 1989; 99 Suppl. J: S38–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables. J Clin Psychopharmacol. 1991; 11: 296–301.PubMedCrossRefGoogle Scholar
  49. 49.
    Hasenack HG, Otjens TCM. Enzyme induction and its reversibility in liver of rats after repeated oral administration of Org 3770 [Report no. 2124]. Oss: N.V. Organon, 1987. (Data on file).Google Scholar
  50. 50.
    Preskorn SH. Selection of an antidepressant: mirtazapine. J Clin Psychiatry. 1997; 58 Suppl. 6: 3–8.PubMedGoogle Scholar
  51. 51.
    Loonen, AJM, Doorschot CH, Oostelbos MCJM, et al. Lack of drug interactions between mirtazapine and risperidone in psychiatric patients: a pilot study. Eur Neuropsychopharmacol. 1999; 10: 51–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Preskorn SH, Omo K, Magnus R, et al. Immediate crossover from fluoxetine to mirtazapine. Biol Psychiatry. 1997; 41: 96S.Google Scholar
  53. 53.
    Mercer AJ. The effects of ethanol alone and its interactions with other compounds on the dynamics of the saccadic eye movement system [thesis]. Cardiff: Department of Medicine, University of Wales, 1992: 202–55.Google Scholar
  54. 54.
    Mattila M, Mattila MJ, Vrijmoed-de Vries M, et al. Actions and interactions of psychotropic drugs on human performance and mood: single doses of Org 3770, amitriptyline and diazepam [Study 85148, Report No. 2468]. Oss: N.V. Organon, 1989. (Data on file).Google Scholar
  55. 55.
    Delbressine L, Dahl ML, Van den Wildenberg HM, et al. In vivo study in humans on disposition of the enantiomers and metabolites of mirtazapine [abstract] 10th European College of Neuropsychopharmacology Congress; 1997 Sep 13–17; Vienna, 1.034.Google Scholar
  56. 56.
    De Boer T, Ruigt GSF, Berendsen HHG. The alpha-2-selective adrenoceptor antagonist Org 3770 (Mirtazapine, Remeron) enhances noradrenergic and serotonergic transmission. Hum Psychopharmacol 1995; 10 Suppl.: S107–18.CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Cees J. Timmer
    • 1
    Email author
  • J. M. Ad Sitsen
    • 2
  • Leon P. Delbressine
    • 3
  1. 1.Department of Drug Metabolism and KineticsN.V. OrganonOssThe Netherlands
  2. 2.Clinical Development DepartmentN.V. OrganonOssThe Netherlands
  3. 3.Department of Toxicology and Drug DispositionN.V. OrganonOssThe Netherlands

Personalised recommendations