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

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.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).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%.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.