The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics

Abstract

Introduction CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status.

Methods Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PC_Bousman, PC_Hahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine.

Results There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram.

Discussion PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

Keywords

pharmacogenetics - phenoconversion - pharmacokinetics - antidepressants - antipsychotics

• References

• 1 Swen JJ, Wilting I, de Goede AL. et al. Pharmacogenetics: From bench to byte. Clin Pharmacol Ther 2008; 83: 781-787
• 2 Hicks JK, Sangkuhl K, Swen JJ. et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017; 102: 37-44
• 3 Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther 2011; 89: 464-467
• 4 Bousman CA, Stevenson JM, Ramsey LB. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther 2023;
• 5 Cicali EJ, Elchynski AL, Cook KJ. et al. How to integrate CYP2D6 phenoconversion into clinical pharmacogenetics: A tutorial. Clin Pharmacol Ther 2021; 110: 677-687
• 6 The Flockhart Cytochrome P450 Drug-Drug Interaction Table. Updated 2021 https://drug-interactions.medicine.iu.edu/ Accessed 31 March, 2023
• 7 Bousman CA, Wu P, Aitchison KJ. et al. Sequence2Script: A web-based tool for translation of pharmacogenetic data into evidence-based prescribing recommendations. Front Pharmacol 2021; 12
• 8 Kiss ÁF, Vaskó D, Déri MT. et al. Combination of CYP2C19 genotype with non-genetic factors evoking phenoconversion improves phenotype prediction. Pharmacol Rep 2018; 70: 525-532
• 9 Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 2001; 51: 169-173
• 10 Klieber M, Oberacher H, Hofstaetter S. et al. CYP2C19 phenoconversion by routinely prescribed proton pump inhibitors omeprazole and esomeprazole: Clinical implications for personalized medicine. J Pharmacol Exp Ther 2015; 354: 426-430
• 11 Ing Lorenzini K, Desmeules J, Rollason V. et al. CYP450 genotype-phenotype concordance using the Geneva Micrococktail in a clinical setting. Front Pharmacol 2021; 12: 730637
• 12 Scherf-Clavel M, Frantz A, Eckert A. et al. Effect of CYP2D6 pharmacogenetic phenotype and phenoconversion on serum concentrations of antidepressants and antipsychotics: A retrospective cohort study. Int J Clin Pharm 2023;
• 13 Mostafa S, Polasek TM, Sheffield LJ. et al. Quantifying the impact of phenoconversion on medications with actionable pharmacogenomic guideline recommendations in an acute aged persons mental health setting. Front Psychiatry 2021; 12: 724170
• 14 Nahid NA, Johnson JA. CYP2D6 pharmacogenetics and phenoconversion in personalized medicine. Expert Opin Drug Metab Toxicol 2023; 1-17
• 15 Mostafa S, Kirkpatrick CMJ, Byron K. et al. An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. J Neural Transm (Vienna) 2019; 126: 5-18
• 16 Hahn M, Roll SC. The role of phenoconversion in the pharmacogenetics of psychiatric medication. Pharmacogenomics 2023;
• 17 Hahn M, Roll SC. Pharmakogenetik zu erhöhung der arzneimitteltherapiesicherheit. Psychopharmakotherapie 2022; 29: 17-26
• 18 Lima JJ, Thomas CD, Barbarino J. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther 2021; 109: 1417-1423
• 19 Lenoir C, Niederer A, Rollason V. et al. Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics. CPT Pharmacometrics Syst Pharmacol 2022; 11: 30-43
• 20 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 21 Zanardi R, Manfredi E, Montrasio C. et al. Pharmacogenetic-guided treatment of depression: Real-world clinical applications, challenges, and perspectives. Clin Pharmacol Ther 2021; 110: 573-581
• 22 Scherf-Clavel M, Weber H, Wurst C. et al. Effects of pharmacokinetic gene variation on therapeutic drug levels and antidepressant treatment response. Pharmacopsychiatry 2022;
• 23 Gendiagnostik-Kommission. Richtlinie der Gendiagnostik-Kommission (GEKO) für die Anforderungen an die Qualitätssicherung genetischer Analysen zu medizinischen Zwecken gemäß § 23 Abs. 2 Nr. 4 GenDG. Bundesgesundheitsblatt 2013; 56: 163-168
• 24 Gendiagnostik-Kommission. Richtlinie der Gendiagnostik-Kommission (GEKO) für die Beurteilung genetischer Eigenschaften hinsichtlich ihrer Bedeutung für die Wirkung eines Arzneimittels bei einer Behandlung gemäß §23 Abs. 2 Nr. 1b GenDG. Bundesgesundheitsblatt 2017; 60: 472-475
• 25 CPIC - Clinical Pharmacogenetics Implementation Consortium. 2021. https://cpicpgx.org/; Accessed 08 March, 2022
• 26 For Healthcare Professionals | FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems. 2023. https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems; Accessed 08 Aug, 2023
• 27 RCoreTeam. R: A language and environment for statistical computing., R Core Team. https://www.R-project.org/: R Foundation for Statistical Computing, Vienna, Austria; 2021
• 28 Verhoeven KJ, Simonsen KL, McIntyre LM. Implementing false discovery rate control: Increasing your power. Oikos 2005; 108: 643-647
• 29 PharmGKB. CYP2C19 Frequency Table. 2022. https://www.pharmgkb.org/page/cyp2c19RefMaterials; https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Ffiles.cpicpgx.org%2Fdata%2Freport%2Fcurrent%2Ffrequency%2FCYP2C19_frequency_table.xlsx&wdOrigin=BROWSELINK; Accessed 16 Oct, 2022
• 30 European Medicines Agency. Europa EU Summary of Product Characteristics of Nexium (INN-esomeprazole). 2021. https://www.ema.europa.eu/en/documents/product-information/nexium-control-epar-product-information_en.pdf.; Accessed 07 August 2023
• 31 Springer-Verlag GmbH, Heidelberg. PSIAC. https://www.psiac.de/; Accessed 03 August, 2023
• 32 Gjestad C, Westin AA, Skogvoll E. et al. Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline. Ther Drug Monit 2015; 37: 90-97
• 33 Cicali EJ, Wiisanen K. The importance of phenoconversion when using the CYP2D6 genotype in clinical practice. Pharmacogenomics 2022; 23: 749-752
• 34 Sangkuhl K, Stingl JC, Turpeinen M. et al. PharmGKB summary: venlafaxine pathway. Pharmacogenet Genomics 2014; 24: 62-72
• 35 Whirl-Carrillo M, McDonagh EM, Hebert JM. et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92: 414-417
• 36 Kobayashi K, Ishizuka T, Shimada N. et al. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 1999; 27: 763-766
• 37 Spina E, de Leon J. Clinical applications of CYP genotyping in psychiatry. J Neural Transm (Vienna) 2015; 122: 5-28
• 38 Wang JH, Liu ZQ, Wang W. et al. Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther 2001; 70: 42-47
• 39 PharmGKB. Clinical Guideline Annotations. 2022 https://www.pharmgkb.org/guidelineAnnotations Accessed 06 Jul, 2022
• 40 Swen JJ, Nijenhuis M, de Boer A. et al. Pharmacogenetics: From bench to byte--an update of guidelines. Clin Pharmacol Ther 2011; 89: 662-673
• 41 Brouwer J, Nijenhuis M, Soree B. et al Dutch Pharmacogenetics Working Group DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet 2021;
• 42 Parikh SV, Law RA, Hain DT. et al. Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder. Psychiatry Res 2022; 308: 114354
• 43 Bousman C, Maruf AA, Müller DJ. Towards the integration of pharmacogenetics in psychiatry: A minimum, evidence-based genetic testing panel. Curr Opin Psychiatry 2019; 32: 7-15
• 44 Hole K, Arnestad M, Molden E. et al. Dose-dependent inhibition of CYP2D6 by bupropion in patients with depression. J Clin Psychopharmacol 2021; 41: 281-285
• 45 de Jong LM, Boussallami S, Sánchez-López E. et al. The impact of CYP2C19 genotype on phenoconversion by concomitant medication. Front Pharmacol 2023; 14: 1201906