Nieves Velez de Mendizabal (1, 2), Kimberley Jackson (3), Brian Eastwood (4), Steven Swanson (5), David M. Bender (5), Stephen Lowe (6), Robert R. Bies (1, 2)
(1) Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, IN, USA; (2) Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA; (3) Global PK/PD/Trial Simulation, Eli Lilly and Company, Windlesham UK; (4) Global Statistical Sciences, Eli Lilly and Company, Windlesham UK; (5) Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, USA; (6) Lilly-NUS Centre for Clinical Pharmacology, Eli Lilly and Company, Singapore, Singapore
Objectives: To develop a population PK model able to simultaneously describe citalopram and N-desmethyl citalopram plasma concentrations in rats after IV and PO administration of citalopram.
Methods: Citalopram was administered intravenously (IV) and orally (PO) to Sprague-Dawley rats (mean weight: 285 grams) at different doses: 0.3, 1, 3, and 10-mg/kg IV and 10-mg/kg PO. Plasma samples were collected for citalopram and N-desmethyl citalopram. Data below the limit of quantification BLQ were reported for both compounds at 0.1 ng/mL. All analyses were performed by using NONMEM 7.2 software. BLQ values were included in the analyses and treated as censored information using the M3 method [1]. The Laplacian numerical estimation method was used for parameter estimation. Citalopram and its metabolite were simultaneously modeled for all doses and administration routes. The model was then extended to Wistar rats (mean weight: 497 grams) at different oral doses: 0.3, 1, 3, 10, 30 and 60-mg/kg. Several absorption models were explored (e.g. first, zero order and combined absorptions, Michaelis-Menten, lag time) in combination with dose and/or time covariate effects.
Results: Disposition of citalopram and of its major metabolite was described by a 5-compartment model: a 3-compartment model for citalopram and a 2-compartment for the metabolite. Citalopram clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was best described using a Michaelis-Menten clearance. When the Wistar data were included (over a large range of oral doses), the absorption process revealed its complexity.
Conclusions: As far as we are aware, this is the first combined citalopram and metabolite population PK model to describe IV as well as oral data in rats in the literature. A complex absorption model was required to adequately describe the disposition of citalopram and N-desmethyl citalopram over the large dose range studied herein.
References:
[1] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504.
Reference: PAGE 22 () Abstr 2694 [www.page-meeting.org/?abstract=2694]
Poster: Absorption and Physiology-Based PK