Effect of age, weight, and CYP2C19 genotype on escitalopram exposure

Yuyan Jin, Bruce G. Pollock, Ellen Frank, Giovanni B. Cassano, Paola Rucci, Daniel J. Müller, James L. Kennedy, Rocco Nicola Forgione, Margaret Kirshner, Gail Kepple, Andrea Fagiolini, David J. Kupfer, Robert Bies

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)62-72
Number of pages11
JournalJournal of Clinical Pharmacology
Volume50
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Fingerprint

Citalopram
Genotype
Weights and Measures
Cytochrome P-450 CYP2C19
Pharmacokinetics
Italy
Body Mass Index

Keywords

  • CYP2C19 gene
  • Escitalopram
  • NONMEM
  • Pharmacogenetics
  • Pharmacokinetics
  • SPECTRUM study

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Jin, Y., Pollock, B. G., Frank, E., Cassano, G. B., Rucci, P., Müller, D. J., ... Bies, R. (2010). Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. Journal of Clinical Pharmacology, 50(1), 62-72. https://doi.org/10.1177/0091270009337946

Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. / Jin, Yuyan; Pollock, Bruce G.; Frank, Ellen; Cassano, Giovanni B.; Rucci, Paola; Müller, Daniel J.; Kennedy, James L.; Forgione, Rocco Nicola; Kirshner, Margaret; Kepple, Gail; Fagiolini, Andrea; Kupfer, David J.; Bies, Robert.

In: Journal of Clinical Pharmacology, Vol. 50, No. 1, 01.2010, p. 62-72.

Research output: Contribution to journalArticle

Jin, Y, Pollock, BG, Frank, E, Cassano, GB, Rucci, P, Müller, DJ, Kennedy, JL, Forgione, RN, Kirshner, M, Kepple, G, Fagiolini, A, Kupfer, DJ & Bies, R 2010, 'Effect of age, weight, and CYP2C19 genotype on escitalopram exposure', Journal of Clinical Pharmacology, vol. 50, no. 1, pp. 62-72. https://doi.org/10.1177/0091270009337946
Jin, Yuyan ; Pollock, Bruce G. ; Frank, Ellen ; Cassano, Giovanni B. ; Rucci, Paola ; Müller, Daniel J. ; Kennedy, James L. ; Forgione, Rocco Nicola ; Kirshner, Margaret ; Kepple, Gail ; Fagiolini, Andrea ; Kupfer, David J. ; Bies, Robert. / Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. In: Journal of Clinical Pharmacology. 2010 ; Vol. 50, No. 1. pp. 62-72.
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