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A Population Pharmacokinetic Model for R- And S-citalopram and Desmethylcitalopram in Alzheimer's Disease Patients With Agitation

A Population Pharmacokinetic Model for R- And S-citalopram and Desmethylcitalopram in Alzheimer's Disease Patients With Agitation

Ayman Akil, Robert R Bies, Bruce G Pollock, Dimitrios Avramopoulos, D P Devanand, Jacobo E Mintzer, Anton P Porsteinsson, Lon S Schneider, Daniel Weintraub, Jerome Yesavage, David M Shade, Constantine G Lyketsos

J Pharmacokinet Pharmacodyn. 2016 Feb;43(1):99-109.

PMID: 26611790

Abstract:

The citalopram for Alzheimer's disease trial evaluated citalopram for the management for agitation in Alzheimer's disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient-specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S-citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S-citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer's disease.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP479065026	Citalopram Related Compound H		479065-02-6	Price

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