Impact of the Ultrarapid CYP2C19*17 Allele on Serum Concentration of Escitalopram in Psychiatric Patients

Abstract

Recently, a novel allelic variant of cytochrome P450 2C19 encoding ultrarapid enzyme activity was described (denoted CYP2C19*17). The objective of this study was to evaluate the impact of CYP2C19*17 on serum concentration of escitalopram in psychiatric patients. One hundred and sixty-six patients treated with escitalopram were divided into the following subgroups according to CYP2C19 genotype: CYP2C19*17/*17 (n=7), CYP2C19*1/*17 (n=43), CYP2C19*1/*1 (n=60), CYP2C19*17/def (n=16), CYP2C19*1/def (n=34), and CYP2C19def/def (n=6) (def=defective allele, i.e., CYP2C19*2 or *3). Dose-adjusted serum concentrations of escitalopram were compared using the CYP2C19*1/*1 subgroup as reference. Geometric mean of the escitalopram serum concentration was 42% lower in patients homozygous for CYP2C19*17 (P<0.01) and 5.7-fold higher in subjects homozygous for defective CYP2C19 alleles (P<0.001). Of the heterozygous subgroups, only CYP2C19*1/def was significantly different from CYP2C19*1/*1 (P<0.001). In conclusion, a homozygous CYP2C19*17 genotype is associated with lower serum concentration of escitalopram, which might imply increased risk of therapeutic failure.

Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

“…The exact times of blood sampling after the drug has been administered are crucial when estimating C max and t max , and differences in these parameters are, therefore, not of great significance. In a study based on data from therapeutic drug monitoring (TDM) files of a Norwegian psychiatric population, a 5.7-fold increase of dose-adjusted serum concentrations of escitalopram was found in subjects homozygous for defective CYP2C19 alleles compared to subjects carrying two functional alleles [19]. This difference from our findings may be due to differences in sample size or populations.…”

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

“…One could speculate that the overall CYP2C19 activity of a CYP2C19*2/*17 subject would be comparable to wild type, because of the presence of one deficient and one highactivity allele. Although our data seem to fit this hypothesis, it was previously found that the CYP2C19*17 allele is of quantitatively less importance than the defective CYP2C19*2 and *3 alleles in the metabolism of omeprazole, 21 escitalopram 19 and sertraline. 27 Patients with a combined CYP2C19*17/defective genotype showed higher dose-corrected escitalopram serum concentrations, 19 and higher dose-adjusted serum concentrations of sertraline and its primary metabolite N-desmethyl sertraline, 27 as compared with CYP2C19*1/*1 patients.…”

“…Although our data seem to fit this hypothesis, it was previously found that the CYP2C19*17 allele is of quantitatively less importance than the defective CYP2C19*2 and *3 alleles in the metabolism of omeprazole, 21 escitalopram 19 and sertraline. 27 Patients with a combined CYP2C19*17/defective genotype showed higher dose-corrected escitalopram serum concentrations, 19 and higher dose-adjusted serum concentrations of sertraline and its primary metabolite N-desmethyl sertraline, 27 as compared with CYP2C19*1/*1 patients. Interestingly, it was recently shown that the presence of the CYP2C19*17 allele is significantly associated with better platelet response to clopidogrel, without significant interaction with the CYP2C19*2 allele, suggesting that the CYP2C19*17 allele influences platelet response independently from the *2 allele.…”

“…17,19,21,22 It was shown that healthy CYP2C19*17/*17 individuals experience a decrease of 52% in systemic omeprazole exposure as compared with healthy wild-type subjects, 21 and it was postulated that *17/*17 individuals would require a 50% increase in escitalopram dose in order to achieve drug exposures similar to *1/*1 subjects. 19 The primary aim of this study was to explore whether the presence of the CYP2C19*17 allele is also correlated with altered imipramine metabolism. A total of 178 depressed psychiatric patients treated with imipramine were dosetitrated towards an imipramine þ desipramine target level, and dose-corrected drug plasma concentrations were calculated, assuming linear pharmacokinetics as previously described.…”

“…[18][19][20] It is associated with increased gene transcription and thus faster metabolism of CYP2C19 substrates mephenytoin, omeprazole, voriconazole and escitalopram. 17,19,21,22 In contrast to defective CYP2C19*2 and *3 alleles, CYP2C19*17 may thus be associated with ultrarapid metabolism and, therefore, therapeutic failure upon proton pump inhibitor, antifungal or antidepressant treatment. 17,23 The primary aim of this study was to investigate whether the CYP2C19*17 genotype is also correlated with altered imipramine pharmacokinetics.…”