Skip to main content
SpringerLink
Log in

Population pharmacokinetic analysis of mirtazapine

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Mirtazapine belongs to the new generation of antidepressants that is commonly used in clinical routine. Therefore, we feel it mandatory to control compliance in the context of non-response, adverse events or other clinical situations by means of plasma concentration measurements. While controlled clinical studies have evaluated the effect of individual covariates on the pharmacokinetics of mirtazapine, our analysis aims to identify covariates within a naturalistic clinical setting.

Methods

We performed non-linear mixed-effects modelling with data from 65 depressed inpatients whose plasma concentrations were measured weekly during their stay in hospital. Each patient’s age, height, weight, co-medication, alcohol, coffee and cigarette consumption, weekly serum creatinine concentrations, liver enzyme activity, blood pressure and pulse was noted. From 49 patients, the genotype of cytochrome P 450 (CYP) isoenzymes 2D6, 2C9 and 2C19 was analysed.

Results

The clearance of CYP2D6 intermediate metabolisers was reduced by 26% compared with extensive metabolisers. No other factor significantly influenced the clearance of these patients.

Conclusion

The variability of mirtazapine plasma concentrations in clinical routine is caused to a relevant degree by CYP2D6. This should be taken into account when therapeutic drug monitoring is carried out to check treatment adherence or when a special clinical situation, such as co-morbidity and add-on medication, demands careful dosing of this drug.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bremner JD (1995) A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatr 56:519–525

    CAS  Google Scholar 

  2. Claghorn JL, Lesem MD (1995) A double-blind placebo-controlled study of mirtazapine in depressed outpatients. J Affect Disord 34:165–171

    Article  CAS  PubMed  Google Scholar 

  3. Smith WT, Glaudin V, Panagides J, Gilvary E (1990) Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depression. Psychopharmacol Bull 26:191–196

    CAS  PubMed  Google Scholar 

  4. Khan MC (1994) A randomised, double-blind, placebo-controlled, 5-weeks’ study of mirtazapine and placebo in hospitalized patients with major depression. Eur Neuropsychopharmacol 4:145–150

    Article  PubMed  Google Scholar 

  5. Vartiainen H, Leinonen E (1994) Double-blind study of mirtazapine and placebo in hospitalized patients with major depression. Eur Neuropsychopharmacol 4:145–150

    Article  PubMed  Google Scholar 

  6. Zivkov M, de Jongh GD (1995) Mirtazapine versus amitriptyline: a 6-week randomized double-blind multicentre trial in hospitalized depressed patients. Hum Psychopharmacol 10:173–180

    Google Scholar 

  7. Mullin J, Lodge A, Bennie E, McCready R, Singh Batt G, Fenton G (1996) A multicentre, double-blind, amitriptyline-controlled study of mirtazapine in patients with major depression. J Psychopharmacol 10:235–240

    CAS  Google Scholar 

  8. Richou H, Ruimy P, Charbaut J, Delisle JP, Brunner H, Patris M (1995) A multicentre, double-blind, clomipramine-controlled efficacy and safety study of mirtazapine. Hum Psychopharmacol 10:263–271

    CAS  Google Scholar 

  9. Marttila M, Jääskelainen J, Järvi R, Romanov M, Miettinen E, Sorri P, Ahlfors U, Zivkov M (1995) A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharmacol 6:441–446

    Article  Google Scholar 

  10. Timmer CJ, Sitsen JM, Delbressine LP (2000) Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 38:461–474

    CAS  PubMed  Google Scholar 

  11. Timmer CJ, Lohmann AAM, Mink CPA (1995) Pharmacokinetic dose-proportionality study at steady-state of mirtazapine from Remeron® tablets. Hum Psychopharmacol 10:S97–S106

    CAS  Google Scholar 

  12. Kasper S, Praschak-Rieder N, Tauscher J, Wolf R (1997) A risk-benefit assessment of mirtazapine in the treatment of depression. Drug Saf 17:251–64

    CAS  PubMed  Google Scholar 

  13. Grasmäder K, Lohmann PL, Kuss HJ, Laux G, Hiemke C, Rao ML (2003) Therapeutisches Drug-Monitoring von Antidepressiva—therapeutischer und gesundheitsökonomischer Nutzen. Med Mol Pharm 26:162–164

    Google Scholar 

  14. World Health Organization (1992) International Statistical Classification of Diseases and Related Health Problems, 1989 Revision, Geneva

  15. Frahnert C, Rao ML, Grasmäder K (2003) Determination of eighteen antidepressants, four antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring. J Chromatogr B Biomed Sci Appl 794:35–47

    Article  CAS  Google Scholar 

  16. Brockmöller J, Rost KL, Gross D, Schenkel A, Roots I (1995) Phenotyping of CYP2C19 with enantiospecific HPLC-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 G-->A-splice site mutation. Pharmacogenetics 5:80–88

    PubMed  Google Scholar 

  17. de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422

    PubMed  Google Scholar 

  18. Broly F, Marez D, Sabbagh N, Legrand M, Millecamps S, Lo Guidice JM, Boone P, Meyer UA (1995) An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics 5:373–384

    CAS  PubMed  Google Scholar 

  19. Steen VM, Andreassen OA, Daly AK, Tefre T, Borresen AL, Idle JR, Gulbrandsen AK (1995) Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology Pharmacogenetics 5:215–223

  20. Løvlie R, Daly AK, Molven A., Idle JR, Steen VM (1996) Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Lett 392:30–34

    Article  PubMed  Google Scholar 

  21. WinNonMix™ Reference Guide (1999) Pharsight Cooperation, Mountain View, California

  22. Franke EK, Ritschel WA (1976) Quick estimation of the absorption rate constant for clinical purposes using a nomograph. Drug Intel Clin Pharm 10:77–82

    CAS  Google Scholar 

  23. Voortman G, Paanakker JE (1995) Bioavailability of mirtazapine from Remeron® tablets after single and multiple oral dosing. Hum Psychopharmacol 10[Suppl]:83–96

    Google Scholar 

  24. Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic--pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm. 20:511–528

    Google Scholar 

  25. Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Mörike K, Stuven T, Eichelbaum M (1998) Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 8:15–26

    CAS  PubMed  Google Scholar 

  26. Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96:1816–1819

    CAS  PubMed  Google Scholar 

  27. Xie HG, Stein CM, Wilkinson GR, Flockhart DA, Wood AJ (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4’-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549

    CAS  PubMed  Google Scholar 

  28. Timmer CJ, Paanakker JE, van Hal HJM (1996) Pharmacokinetics of mirtazapine from orally administered tablets: influence of gender, age and treatment regimen. Hum Psychopharmacol 11:497–509

    Article  Google Scholar 

  29. Delbressine LPC, Moonen MEG, Kaspersen FM, Wagenaars GN, Jacobs PL, Timmer CJ, Paanakker JE, van Hal HJM, Voortman G (1998) Pharmacokinetics and biotransformation of mirtazapine in healthy volunteers. Clin Drug Invest 15:45–55

    CAS  Google Scholar 

  30. Störmer E, von Moltke LL, Shader RI, Greenblatt DJ (2000) Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6 and 3A4. Drug Metab Dispos 28:1168–1175

    PubMed  Google Scholar 

  31. Raimundo S, Fischer J, Eichelbaum M, Griese EU, Schwab M, Zanger UM (2000) Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6. Pharmacogenetics 10:577–581

    Article  CAS  PubMed  Google Scholar 

  32. Dahl ML, Voortman G, Alm C, Elwin CE, Delbressine L, Vos R, Bogaards JJP, Bertilson L (1997) In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest 13:37–46

    CAS  Google Scholar 

  33. Anttila SAK, Rasanen I, Leinonen EVJ (2001) Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold. Ann Pharmacother 35:1221–1223

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The study was supported by the “Kompetenznetz Depression/Suizidalität” of the German Ministry of Education and Research (BMBF).

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53121 , Bonn, Germany

    Katja Grasmäder, Petra Louise Verwohlt, Kai-Uwe Kühn, Olrik von Widdern, Astrid Zobel, Marcella Rietschel, Wolfgang Maier & Marie Luise Rao

  2. Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 , Bonn, Germany

    Ulrich Jaehde

  3. Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, 55131 , Mainz, Germany

    Aleksandra Dragicevic & Christoph Hiemke

Authors
  1. Katja Grasmäder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petra Louise Verwohlt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kai-Uwe Kühn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aleksandra Dragicevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olrik von Widdern
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Astrid Zobel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph Hiemke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcella Rietschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wolfgang Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ulrich Jaehde
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marie Luise Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie Luise Rao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grasmäder, K., Verwohlt, P.L., Kühn, KU. et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 60, 473–480 (2004). https://doi.org/10.1007/s00228-004-0737-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-004-0737-0

Keywords

Search

Navigation