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Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

ABSTRACT: Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26-1.50) and 2.68-fold (95% CI 2.16-3.31) in CYP2C19 IMs and PMs, respectively (p?

SUBMITTER: Braten LS

PROVIDER: S-EPMC6969041 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

Bråten Line S LS Haslemo Tore T Jukic Marin M MM Ingelman-Sundberg Magnus M Molden Espen E Kringen Marianne K MK

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20191024 3

Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included ...[more]

PMID: 31649299

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Project description:The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, body mass index, sex, race, and clinical site were evaluated as possible covariates. In total, 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A 1-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L, respectively. CYP2C19 genotype, weight, and age had a significant effect on CL/F, and patient body mass index affected estimated V/F. Patients from Pisa, Italy, had significantly lower clearances than patients from Pittsburgh that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Postprocessed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19(*)2 or (*)3 (n = 82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous (*)2 or (*)3 ((*)17/(*)2, (*)17/(*)3, (*)1/(*)2, (*)1/(*)3, (*)2/(*)2, (*)2/(*)3, and (*)3/(*)3, n = 46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n = 45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30 to 50 years (n = 84) and older than 50 years of age (n = 43), respectively. CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. These variables may affect patient tolerance of this antidepressant and may provide important information in the effort to tailor treatments to patients' individual needs.

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Dataset Information

Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

Publications

Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

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