Escitalopram

Absorption

The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day.
With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose.
Absorption
The absolute bioavailability of citalopram is about 80% relative to an intravenous dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.
Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food.
Distribution
The binding of escitalopram to human plasma proteins is approximately 56%. The volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.
Elimination
Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27 to 32 hours. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.
Metabolism
Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects.
In vitrostudies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT
1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D
1-5), histamine (H
1-3), muscarinic (M
1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na
+, K
+, Cl
-, and Ca
++channels.
In vitrostudies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.
Excretion
Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively.
Specific Populations
Pediatric Patients
Pediatric patients 7 to 11 years of age: Based on population PK simulations, following multiple dosing of 20 mg/day escitalopram, steady-state C
maxand AUC
tauof escitalopram were increased by 93% and 86%, respectively in pediatric patients with GAD 7 to 11 years of age compared to adults.
Pediatric patients 12 to 17 years of age: In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and C
maxincreased by 26% in healthy pediatric subjects 12 to 17 years of age compared to adults. Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state C
maxand AUC were similar in pediatric patients 12 to 17 years of age with MDD compared to adults
[see
Use in Specific Populations (8.4)]
.
Geriatric Patients
Escitalopram pharmacokinetics in subjects ≥ 65 years of age were compared to adults in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and C
maxwas unchanged
[see
Dosage and Administration (2.5),
Use in Specific Populations (8.5)].
Male and Female Patients
Based on data from single- and multiple-dose studies measuring escitalopram in elderly, young adults, and adolescents, no dosage adjustment on the basis of gender is needed.
Patients with Hepatic Impairment
Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects
[see
Dosage and Adm …