title: A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer's disease patients with agitation.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: Ayman
authors.initials: A
authors.lastname: Akil
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA. robertbi@buffalo.edu.|Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA. robertbi@buffalo.edu.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.affiliation: Campbell Institute, CAMH, University of Toronto, Toronto, ON, Canada.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.affiliation: Division of Geriatric Psychiatry, New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Devanand
authors.affiliation: Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, SC, USA.
authors.forename: Jacobo E
authors.initials: JE
authors.lastname: Mintzer
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Anton P
authors.initials: AP
authors.lastname: Porsteinsson
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
authors.affiliation: Stanford University School of Medicine and VA Palo Alto Health Care System, Stanford, CA, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Yesavage
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Shade
authors.affiliation: Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Lyketsos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000465:Algorithms; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D000928:Antidepressive Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D015283:Citalopram / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D011595:Psychomotor Agitation / Q000150:complications / Q000378:metabolism*; D012727:Sex Characteristics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; C046304:desmethylcitalopram
keywords: Agitation; Alzheimer’s disease; Citalopram; Pharmacokinetics