Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

AIMS: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. METHODS: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. RESULTS: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CONCLUSIONS: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients - a study based on a cohort of 19,742 patients.

BACKGROUND: For a decade, patients have been advised against using high citalopram- and escitalopram-doses due to risk for ventricular arrhythmia and cardiac arrest. Still, these drugs are widely used to treat depression and anxiety especially in older patients. It is unclear why they are cardiotoxic and at what serum concentrations patients are at risk for arrhythmias. Thus, how many patients that are at risk for iatrogenic cardiac arrest is unknown. METHODS: We studied the arrhythmogenic effects of citalopram, escitalopram and their metabolites on human cardiomyocytes. Concentrations showing pro-arrhythmic activity were compared with observed drug and metabolite serum concentrations in a cohort of 19,742 patients (age 12-105 years) using escitalopram or citalopram in Norway (2010-2019). As arrhythmia-risk is related to maximum serum concentration, this was simulated for different age-groups from the escitalopram patient material. FINDINGS: Therapeutic concentrations of both citalopram and escitalopram but not their metabolites showed pro-arrhythmic changes in the human cardiac action potential. Due to age-dependent reduction of drug clearance, the proportion of patients above threshold for arrhythmia-risk increased with age. 20% of patients >65 years were predicted to reach potentially pro-arrhythmic concentrations, following intake of 10 mg escitalopram. INTERPRETATION: All patients that are using escitalopram or citalopram and have genetic disposition for acquired long-QT syndrome, are >65 years, are using additional pro-arrhythmic drugs or have predisposition for arrhythmias, should be monitored with therapeutic drug monitoring (TDM) to avoid exposure to potentially cardiotoxic concentrations. Serum concentrations should be kept below 100 nM, to reduce arrhythmia-risk. FUNDING: This study was funded by The Research Council of Norway (project number: 324062).

Identification of Escitalopram Metabolic Ratios as Potential Biomarkers for Predicting CYP2C19 Poor Metabolizers.

BACKGROUND: Escitalopram is metabolized by CYP2C19 to N-desmethyl escitalopram and escitalopram propionic acid. The primary aims of this study were to investigate the impact of the CYP2C19 phenotype on metabolic ratios of escitalopram in vivo and propose a biomarker for the CYP2C19 phenotype in patients treated with escitalopram. METHODS: Median steady-state serum metabolite/parent drug ratio of N-desmethyl escitalopram and escitalopram propionic acid was investigated across CYP2C19 genotype-translated phenotype groups. The receiver operator characteristics method and the area-under-the-receiver-operator-characteristics curve was used to determine the best suited metabolic ratio for detecting CYP2C19 poor metabolizers (PMs). RESULTS: A total of 441 patients were included in the study. The N-desmethyl escitalopram/escitalopram ratio was 67% and 44% lower in CYP2C19 PMs and intermediate metabolizers (IMs), respectively, than normal metabolizers. Furthermore, the ability of the ratio to predict CYP2C19 PMs was 92%. A metabolic ratio of <0.24 was detected in 8 of 8 PMs in the study, indicating that it is a promising biomarker of reduced CYP2C19 activity. The escitalopram propionic acid/escitalopram ratio was 77% and 48% lower in CYP2C19 PMs and IMs, respectively; however, the ability of the ratio to detect CYP2C19 PMs was only 87%. CONCLUSIONS: These findings suggest that DECT/ECT reflects CYP2C19 activity, and a metabolic ratio of <0.24 strongly predicts CYP2C19 PM phenotype. The ratio could be a valuable alternative to genotyping in personalized dosing of escitalopram and possibly other CYP2C19 substrates. The escitalopram propionic acid/escitalopram ratio was also associated with CYP2C19 activity; however, the ratio was inferior to the DECT/ECT at predicting PMs.