The pharmacokinetics of escitalopram in patients with hepatic impairment.
The effect of hepatic impairment on the pharmacokinetics of escitalopram was determined by means of nonlinear mixed effect modeling, considering both the Child-Pugh classification (and its components) and cytochrome P450 2C19 (CYP2C19) activity. Twenty-four subjects were grouped according to their Child-Pugh score as healthy, with mild hepatic impairment or with moderate hepatic impairment. The subjects were administered a single oral dose of escitalopram 20 mg, and blood was sampled up to 168 hours after dosage. The serum concentration of escitalopram was determined and the pharmacokinetics assessed by nonlinear mixed effect modeling. The CYP2C19 activity was measured from the urinary excretion ratio of S/R-mephenytoin. All subjects tolerated the treatment well, and no serious adverse events were reported. Predicted mean area under the curve from zero to infinity (AUC(inf)) values were 51% and 69% higher for patients with mild and moderate hepatic impairment (Child-Pugh classification), respectively, compared with healthy subjects. The best-fitting model showed an influence of CYP2C19 activity on clearance and body weight on the volume of distribution for escitalopram. CYP2C19 activity is a better predictor of escitalopram clearance than is Child-Pugh classification.
Areberg
Johan
J
H Lundbeck A/S, Copenhagen, Denmark. joar@lundbeck.com
Christophersen
Jacob Strøyer
JS
Poulsen
Mette Nøhr
MN
Larsen
Frank
F
Molz
Karl-Heinz
KH
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood; D015283:Citalopram / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000097:blood
D015283:Citalopram; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19