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Clinical Pharmacokinetics

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01-09-2014 | Systematic Review

Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis

Authors: Ming Chang, Gunnel Tybring, Marja-Liisa Dahl, Jonatan D. Lindh

Published in: Clinical Pharmacokinetics | Issue 9/2014

Abstract

Background

Citalopram and escitalopram, selective serotonin reuptake inhibitors, are primarily metabolized by cytochrome P450 (CYP) 2C19, which is a highly polymorphic enzyme known to cause inter-individual differences in pharmacokinetics. However, the impact of CYP2C19 polymorphisms on citalopram or escitalopram exposure has yet to be fully clarified, especially with regard to the quantitative impact of the CYP2C19*17 allele.

Objective

The objective of this study was to quantify the effect of functional CYP2C19 allele variants on citalopram/escitalopram exposure.

Methods

We performed a systematic review and meta-analysis with a structured search algorithm and eligibility criteria for including related studies, calculating the change of citalopram or escitalopram exposure associated with CYP2C19*2, *3, and *17 as compared with CYP2C19*1 using fixed-effect and random-effects models. Assessment of publication bias was performed by means of funnel plots and sensitivity analysis using meta-regressions. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013004106.

Results

Sixteen studies from 14 publications met the inclusion criteria. Eligible studies included 847 patients from psychiatric patient trials and 140 healthy subjects from pharmacokinetic studies. Compared to subjects with the EM/EM (CYP2C19*1/*1) genotype, the exposure to (es)citalopram increased by 95 % (95 % CI 40–149, p < 0.0001) in the poor metabolizer (PM)/PM (CYP2C19*2 or *3/*2 or *3), 30 % (95 % CI 4–55, p < 0.05) in the extensive metabolizer (EM)/PM (CYP2C19*1/*2 or *3), and 25 % (95 % CI 1–49, p < 0.05) in the ultrarapid metabolizer (UM)/PM (CYP2C19*17/*2 or *3) groups. In contrast, the exposure to (es)citalopram decreased by 36 % (95 % CI 27–46, p < 0.0001) in the UM/UM (CYP2C19*17/*17) and by 14 % (95 % CI 1–27, p < 0.05) in the UM/EM (CYP2C19*17/*1).

Interpretation

This is the first meta-analysis based on a systematic review of accumulated information that addresses the relationship between CYP2C19 genotypes and the exposure to citalopram or escitalopram. All functional CYP2C19 genotype groups demonstrated significant effects on (es)citalopram exposure. The findings based on our pooled analysis are likely to help in understanding the inter-individual variability in the exposure to citalopram and escitalopram in psychiatric patients and to facilitate dose selection, particularly for the homozygous carriers of CYP2C19*2 or *3 (loss of function) and CYP2C19*17 (gain of function) alleles. The results could improve individualization of citalopram or escitalopram therapy and could also be used for physiologically based pharmacokinetic modeling as well as pharmacokinetic/pharmacodynamic modeling.

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Brøsen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol. 2001;11(4):275–83.PubMedCrossRef

Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345–50.PubMedCrossRef

Drewes P, Tjijssen I, Mengel H, Larsen F. A single-dose cross-over pharmacokinetic study comparing racemic citalopram (40 mg) with the S-enantiomer of citalopram (escitalopram, 20 mg) in healthy male subjects. 41st Annual Meeting of the New Clinical Drug Evaluation Unit; 28–31 May 2001; Phoenix.

Burke WJ. Escitalopram. Expert Opin Investig Drugs. 2002;11(10):1477–86.PubMedCrossRef

Rochat B, Amey M, Gillet M, Meyer UA, Baumann P. Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics. 1997;7(1):1–10.PubMedCrossRef

Chang M, Tybring G, Dahl ML, Götharson E, Sagar M, Seensalu R, et al. Interphenotype differences in disposition and effect on gastrin levels of omeprazole—suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol. 1995;39(5):511–8.PubMedCentralPubMedCrossRef

Stingl JC, Brockmöller J, Viviani R. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry. 2013;18(3):273–87.PubMedCrossRef

Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103–13.PubMedCrossRef

Ohlsson Rosenborg S, Mwinyi J, Andersson M, Baldwin RM, Pedersen RS, Sim SC, et al. Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol. 2008;64(12):1175–9.PubMedCrossRef

10.

Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E. Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther. 2008;83(2):322–7.PubMedCrossRef

11.

Tsai MH, Lin KM, Hsiao MC, Shen WW, Lu ML, Tang HS, et al. Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics. 2010;11(4):537–46.PubMedCrossRef

12.

de Vos A, van der Weide J, Loovers HM. Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J. 2011;11(5):359–67.PubMedCrossRef

13.

Huezo-Diaz P, Perroud N, Spencer EP, Smith R, Sim S, Virding S, et al. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol. 2012;26(3):398–407.PubMedCrossRef

14.

Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry. 2005;66(8):974–81.PubMedCrossRef

15.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.PubMedCrossRef

16.

Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements–a systematic review and meta-analysis. Eur J Clin Pharmacol. 2009;65(4):365–75.PubMedCrossRef

17.

R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2012. ISBN 3-900051-07-0, http://www.R-project.org/. Accessed 14 Aug 2014

18.

Rudberg I, Hendset M, Uthus LH, Molden E, Refsum H. Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Ther Drug Monit. 2006;28(1):102–5.PubMedCrossRef

19.

Herrlin K, Yasui-Furukori N, Tybring G, Widén J, Gustafsson LL, Bertilsson L. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol. 2003;56(4):415–21.PubMedCentralPubMedCrossRef

20.

Sindrup SH, Brøsen K, Hansen MG, Aaes-Jørgensen T, Overø KF, Gram LF. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit. 1993;15(1):11–7.PubMedCrossRef

21.

Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol. 1996;16(4):307–14.PubMedCrossRef

22.

Carlsson B, Olsson G, Reis M, Walinder J, Nordin C, Lundmark J, et al. Enantioselective analysis of citalopram and metabolites in adolescents. Ther Drug Monit. 2001;23(6):658–64.PubMedCrossRef

23.

Yu BN, Chen GL, He N, Ouyang DS, Chen XP, Liu ZQ, et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19. Drug Metab Dispos. 2003;31(10):1255–9.PubMedCrossRef

24.

Noehr-Jensen L, Zwisler ST, Larsen F, Sindrup SH, Damkier P, Nielsen F, et al. Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker. Eur J Clin Pharmacol. 2009;65(9):887–94.PubMedCrossRef

25.

Fudio S, Borobia AM, Piñana E, Ramírez E, Tabarés B, Guerra P, et al. Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol. 2010;626(2–3):200–4.PubMedCrossRef

26.

Jiang T, Rong Z, Xu Y, Chen B, Xie Y, Chen C, et al. Pharmacokinetics and bioavailability comparison of generic and branded citalopram 20 mg tablets: an open-label, randomized-sequence, two-period crossover study in healthy Chinese CYP2C19 extensive metabolizers. Clin Drug Investig. 2013;33(1):1–9.PubMedCrossRef

27.

Chang M, Dahl ML, Tybring G, Götharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics. 1995;5(6):358–63.PubMedCrossRef

28.

Sim SC, Kacevska M, Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J. 2013;13(1):1–11.PubMedCrossRef

Title: Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis
Authors: Ming Chang
Gunnel Tybring
Marja-Liisa Dahl
Jonatan D. Lindh
Publication date: 01-09-2014
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 9/2014
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0162-1

2024 ASCO Annual Meeting

Springer Medicine

Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis

Abstract

Background

Objective

Methods

Results

Interpretation

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Objective

Methods

Results

Interpretation

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