caa a22 4500 60553375X CHVBK 20210128100839.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s10928-015-9448-7 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9448-7 A population PK model for citalopram and its major metabolite, N-desmethyl citalopram, in rats [Elektronische Daten] [Nieves Velez de Mendizabal, Kimberley Jackson, Brian Eastwood, Steven Swanson, David Bender, Stephen Lowe, Robert Bies] A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague-Dawley (SD) rats at doses: 0.3, 1, 3, and 10mg/kg IV and 10mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quantification limit (BLQ <0.1ng/mL) were included in the analyses and treated as censored information. The disposition of citalopram was best described by a 3-compartment model and its desmethyl metabolite by a 2-compartment model. Several models for the absorption rate were explored (e.g. first, zero order and combined first and zero order absorption, Michaelis-Menten, lag time) in combination with dose and/or time dependent covariate effects. Dose dependent oral bioavailability properties were also identified in this analysis. Citalopram IV clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was adequately described using a Michaelis-Menten clearance with different parameters depending on the strain. This analysis demonstrates a very complex absorption/metabolism process explaining the highly non-linear pharmacokinetics observed across all the doses. This is the first combined parent/metabolite population PK analysis in both SD and Wistar rats over a wide range of IV and PO dosages for citalopram, a compound that exhibits highly nonlinear oral pharmacokinetics in rats. Springer Science+Business Media New York, 2015 Citalopram nationallicence N-desmethyl citalopram nationallicence Metabolite nationallicence NONMEM nationallicence PK : Pharmacokinetic nationallicence PO : per os (oral administration) nationallicence IV : Intravenous nationallicence SD : Sprague-Dawley nationallicence BLQ : Below the limit of quantification nationallicence SSRI : Selective serotonin reuptake inhibitor nationallicence MM : Michaelis-Menten nationallicence Velez de Mendizabal Nieves Global PK/PD and Pharmacometrics, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, 46285, Indianapolis, IN, USA aut Jackson Kimberley Global PK/PD and Pharmacometrics, Eli Lilly and Company, Windlesham, UK aut Eastwood Brian Global Statistical Sciences, Eli Lilly and Company, Windlesham, UK aut Swanson Steven Drug Disposition, Eli Lilly and Company, Indianapolis, IN, USA aut Bender David Product Design and Developability, Eli Lilly and Company, Indianapolis, IN, USA aut Lowe Stephen Lilly-NUS Centre for Clinical Pharmacology, Eli Lilly and Company, Singapore, Singapore aut Bies Robert Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/6(2015-12-01), 721-733 1567-567X 42:6<721 2015 42 10928 https://doi.org/10.1007/s10928-015-9448-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9448-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Velez de Mendizabal Nieves Global PK/PD and Pharmacometrics, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, 46285, Indianapolis, IN, USA aut NATIONALLICENCE 700 1- Jackson Kimberley Global PK/PD and Pharmacometrics, Eli Lilly and Company, Windlesham, UK aut NATIONALLICENCE 700 1- Eastwood Brian Global Statistical Sciences, Eli Lilly and Company, Windlesham, UK aut NATIONALLICENCE 700 1- Swanson Steven Drug Disposition, Eli Lilly and Company, Indianapolis, IN, USA aut NATIONALLICENCE 700 1- Bender David Product Design and Developability, Eli Lilly and Company, Indianapolis, IN, USA aut NATIONALLICENCE 700 1- Lowe Stephen Lilly-NUS Centre for Clinical Pharmacology, Eli Lilly and Company, Singapore, Singapore aut NATIONALLICENCE 700 1- Bies Robert Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/6(2015-12-01), 721-733 1567-567X 42:6<721 2015 42 10928