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Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups.

Methods

Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40–65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses.

Results

In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups).

Conclusion

This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

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References

  1. Mulsant BH, Ganguli M (1999) Epidemiology and diagnosis of depression in late life. J Clin Psychiatry 60(suppl 20):9–15

    PubMed  Google Scholar 

  2. Norwegian Institute of Public Health, Norwegian Prescription Database. http://www.reseptregisteret.no. Accessed 11 September 2013

  3. Statistics Norway. Population at population censuses in 2001 and 2011, by age. http://www.ssb.no/a/english/kortnavn/fobhoved_en/tab-2012-06-21-02-en.html. Accessed 11 September 2013

  4. Hammer W, Sjöqvist F (1967) Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci 6:1895–1903

    Article  CAS  PubMed  Google Scholar 

  5. Alexanderson B, Evans DAP, Sjöqvist F (1969) Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 4:764–768

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Reis M, Lundmark J, Björk H et al (2002) Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting. Ther Drug Monit 24:545–553

    Article  CAS  PubMed  Google Scholar 

  7. Reis M, Aamo T, Spigset O et al (2009) Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit 31:42–56

    Article  CAS  PubMed  Google Scholar 

  8. Rudberg I, Mohebi B, Hermann M et al (2008) Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharm Ther 83:322–327

    Article  CAS  Google Scholar 

  9. Fogelman SM, Schmider J, Venkatakrishnan K et al (1999) O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacol 20:480–490

    Article  CAS  Google Scholar 

  10. Otton SV, Ball SE, Cheung SW et al (1996) Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 41:149–156

    Article  CAS  PubMed  Google Scholar 

  11. Sindrup SH, Brosen K, Hansen MG et al (1993) Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 15:11–17

    Article  CAS  PubMed  Google Scholar 

  12. Yu BN, Chen GL, He N et al (2003) Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19. Drug Metab Dispos 31:1255–1259

    Article  CAS  PubMed  Google Scholar 

  13. Hermann M, Hendset M, Fosaas K et al (2008) Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin Pharmacol 64:483–487

    Article  CAS  PubMed  Google Scholar 

  14. Shams ME, Arneth B, Hiemke C et al (2006) CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther 31:493–502

    Article  CAS  PubMed  Google Scholar 

  15. Herrlin K, Yasui-Furukori N, Tybring G et al (2003) Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol 56:415–421

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Jin Y, Pollock BG, Frank E et al (2010) Effect of age, weight and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol 50:62–72

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Tsai MH, Lin KM, Hsiao MC et al (2010) Genetic polymorphisms of cytochrome P450 influence metabolism of escitalopram and treatment response. Pharmacogenomics 11:537–546

    Article  CAS  PubMed  Google Scholar 

  18. Waade RB, Molden E, Refsum H et al (2012) Serum concentrations of antidepressants in the elderly. Ther Drug Monit 34:25–30

    Article  CAS  PubMed  Google Scholar 

  19. Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine. http://medicine.iupui.edu/clinpharm/ddis/clinical-table/Accessed 10 March 2014

  20. Rudberg I, Hendset M, Uthus LH et al (2006) Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Ther Drug Monit 28:102–105

    Article  CAS  PubMed  Google Scholar 

  21. Schaeffeler E, Schwab M, Eichelbaum M et al (2003) CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR. Hum Mutat 22:476–485

    Article  CAS  PubMed  Google Scholar 

  22. World Health Organization. Definition of an older or elderly person. http://www.who.int/healthinfo/survey/ageingdefnolder/en/Accessed 20 March 2014

  23. Hiemke C, Baumann P, Bergemann N et al (2011) AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 44:195–235

    Article  Google Scholar 

  24. Lessard É, Yessine MA, Hamelin BA et al (1999) Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9:435–443

    Article  CAS  PubMed  Google Scholar 

  25. Howell C, Wilson AD, Waring WS (2007) Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol 64:192–197

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Johnson EM, Whyte E, Mulsant BH et al (2006) Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiat 14:796–802

    Article  Google Scholar 

  27. TIAFT reference blood level list of therapeutic and toxic substances. September 2004. http://www.gtfch.org/cms/images/stories/Updated_TIAFT_list_202005.pdf. Accessed 25 September 2013

  28. Adis data information BV (2006) Dose adjustment of drugs with high hepatic extraction are required in patients with severe liver disease. Drugs Ther Perspect 22:23–26, 1172-0360/06/0005-0023

    Google Scholar 

  29. Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41:67–76

    Article  CAS  PubMed  Google Scholar 

  30. Cusack BJ (2004) Pharmacokinetics in older persons. Am J Geriatr Pharmacother 2:274–302

    Article  CAS  PubMed  Google Scholar 

  31. Gutierrez M, Abramowitz W (2001) Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy 21:163–168

    Article  CAS  PubMed  Google Scholar 

  32. Lindh JD, Annas A, Meurling L et al (2003) Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 59:401–406

    Article  CAS  PubMed  Google Scholar 

  33. Kinirons MT, O'Mahony MS (2004) Drug metabolism and ageing. Br J Clin Pharmacol 57:540–544

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Bebia Z, Buch SC, Wilson JW et al (2004) Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 76:618–627

    Article  CAS  PubMed  Google Scholar 

  35. Hunt CM, Westerkam WR, Stave GM (1992) Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 44:275–283

    Article  CAS  PubMed  Google Scholar 

  36. Harris RZ, Benet LZ, Schwartz JB (1995) Gender effects in pharmacokinetics and pharmacodynamics. Drugs 50:222–239

    Article  CAS  PubMed  Google Scholar 

  37. McCune JS, Lindley C, Decker JL et al (2001) Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol 41:723–731

    Article  CAS  PubMed  Google Scholar 

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Contribution of authors

All authors provided substantial contributions to the conception and design of the study and were responsible for interpretation of data contained within this manuscript. HLM was the primary contributor of the data collection. RBW was responsible for data processing and statistical analyses and also prepared the initial draft of the manuscript. All authors revised the manuscript critically for important intellectual content and read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85 Vinderen, 0319, Oslo, Norway

    Ragnhild Birkeland Waade & Espen Molden

  2. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Monica Hermann, Hanne Lewis Moe & Espen Molden

Authors
  1. Ragnhild Birkeland Waade
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  2. Monica Hermann
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  3. Hanne Lewis Moe
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  4. Espen Molden
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Corresponding author

Correspondence to Ragnhild Birkeland Waade.

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Waade, R.B., Hermann, M., Moe, H.L. et al. Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups. Eur J Clin Pharmacol 70, 933–940 (2014). https://doi.org/10.1007/s00228-014-1696-8

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  • DOI: https://doi.org/10.1007/s00228-014-1696-8

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