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. © 2010 the American College of Clinical Pharmacology.

Jin, Y., Pollock, B.G., Frank, E., Cassano, G.B., Rucci, P., Müller, D.J., et al. (2010). Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. THE JOURNAL OF CLINICAL PHARMACOLOGY, 50(1), 62-72 [10.1177/0091270009337946].

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

FAGIOLINI, A.;
2010-01-01

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. © 2010 the American College of Clinical Pharmacology.
2010
Jin, Y., Pollock, B.G., Frank, E., Cassano, G.B., Rucci, P., Müller, D.J., et al. (2010). Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. THE JOURNAL OF CLINICAL PHARMACOLOGY, 50(1), 62-72 [10.1177/0091270009337946].
File in questo prodotto:
File Dimensione Formato  
Effect_of_Age,_Weight,_and_CYP2C19_Genotype_on_Escitalopram_Exposure.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 479.82 kB
Formato Adobe PDF
479.82 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/12119
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo