Effect of Age, Weight, and CYP2C19 Genotype on Escitalopram Exposure

Abstract

Objective The purpose of this study was to characterize escitalopram population pharmacokinetics (PK)in patients treated for major depression in a cross-national, U.S.-Italian clinical trial. Methods Data from the two sites participating in this trial, conducted at Pittsburgh (USA) and Pisa (Italy) were utilized. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed-effects modeling (NONMEM) was used to model the PK characteristics of escitalopram. One and two compartment models with various random effect implementations were evaluated during model development. Objective function values (OFV) and goodness of fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, BMI, sex, race, and clinical site were evaluated as possible covariates. Results 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A one-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 BMI affected estimated V/F. Pisa, Italy patients had significantly lower clearances than Pittsburgh patients that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Post-processed 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 30-50 years (n=84) and greater than 50 years of age (n=43), respectively. Conclusions CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. Patients with heterogeneous or homogeneous CYP2C19*2 or *3 genotype had significantly lower clearances than patients with other genotypes. CL/F significantly decreased with either increasing age or decreasing body weight. These variables may affect patient tolerance of this antidepressant and, consistent with the NIH emphasis on personalized treatment, may provide important information in the effort to tailor treatments to patients’ individual needs.

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

“…In detail, numerous studies found a correlation between CYP2D6 metabolizing activity and the metabolism of several antidepressants: (a) venlafaxine [94][95][96][97][98][99][100], (b) fluoxetine [101][102][103][104], (c) paroxetine [101,105,106], and (d) nortriptyline [107][108][109][110]. The impact of CYP2C19 metabolizing status on antidepressant pharmacokinetics was also widely replicated for: (a) citalopram [111][112][113], (b) S-citalopram [44,[114][115][116][117], and (c) amitriptyline/nortriptyline [96,118,119]. On the base of this evidence, theoretical dose adjustments were determined according to the individual metabolizing group [120].…”

Escitalopram

“…The pharmacologic properties of escitalopram have been extensively reviewed; [14] therefore, only a brief summary is provided in this section, based on reviews, [14][15][16][17][18] preclinical studies, [19][20][21][22] studies in healthy adolescent [23] or adult [24][25][26][27] volunteers or adult patients with MDD, [28,29] and the US prescribing information. [13] Pharmacodynamic Profile…”

“…[14] No dosage adjustment based on sex is required. [13] Based on data from a US-Italian trial in 172 adult patients with MDD, [29] CYP2C19 genotype and weight significantly altered the clearance of escitalopram. [13] Based on data from a US-Italian trial in 172 adult patients with MDD, [29] CYP2C19 genotype and weight significantly altered the clearance of escitalopram.…”

“…[13] The pharmacokinetic properties of escitalopram in patients with mild to moderate hepatic or renal impairment were not affected to a clinically significant extent; [14] however, caution is recommended for the use of escitalopram in patients with severe hepatic or renal impairment. [29] Potential Drug Interactions For example, after 32 weeks of escitalopram 5-20 mg day, patients without the CYP2C19*2 or CYP2C19*3 allele had a faster drug clearance than patients with heterogeneous or homogenous alleles; higher body mass index was associated with increased estimated volume of distribution.…”

Citalopram for the Treatment of Agitation in Alzheimer Dementia

“…21 More recent interest has focused on the impact of the ε4 allelic variant on response to lipid-lowering treatment 22,23 and antidepressant response. 18 CYP2C19 is known to have variants associated with the metabolism and clearance of citalopram and escitalopram, 19 leading to lower or higher serum concentrations of the drug. It is important to remember that as opposed to most of the genetic studies that have looked at how genes affect the efficacy of antidepressants for treating depressive syndromes, the present study looks at the efficacy of using an antidepressant for treatment of agitation in dementia.…”