Nieves Velez de Mendizabal (1,2), Kimberley Jackson (3), Wesley F Seidel (4), Andrew P. McCarthy (4), Stephen Lowe (5), Brian Eastwood (4), Robert R Bies (1, 2)
(1) Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, IN, USA, (2) Division of Clinical Pharmacology, 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-NUS Centre for Clinical Pharmacology, Eli Lilly and Company, Singapore, Singapore
Objectives: To develop a population kinetic-pharmacodynamic (KPD) model that describes the pattern of sleep and quantifies the sleep changes in Wistar rats after different oral doses of citalopram.
Methods: Citalopram was administered orally (PO) to 91 Wistar rats at different doses: vehicle (n=17), 0.3 (n=8), 1 (n=11), 2.5 (n=8), 5 (n=11), 10 (n=10), 30 (n=18) and 60-mg/kg (n=8). Citalopram and n-desmethylcitalopram concentration measurements were not available in this study, therefore simulated profiles were used derived from a previously published PK model by Velez de Mendizabal et al. [1] for Wistar and Sprague-Dawley rats and used as input to the PD model. No Inter-subject variability was included in those profiles, although weight was taken into account to adjust parameters. Three dependent variables (DV) were defined for estimation. They represent the accumulated minutes in AWAKE, NREM and REM stage. These three DVs were simultaneously modelled during both the baseline (no treatment) and the citalopram/vehicle treatment period. This model was developed in three steps: (i) baseline, (ii) handling effect and (iii) drug effect. The analyses were performed using NONMEM version 7.2 (Icon Development Solutions, Hanover, Maryland). The First Order Conditional Estimation method with the INTERACTION option was used for parameter estimation.
Results: The accumulated number of minutes in AWAKE, NREM and REM stages were described using a 3-compartment model, one per stage, defined by three inter-related zero order rate functions (minutes per hour). Administration of citalopram produced changes in those rates resulting in a new dynamic re-distribution of the accumulated minutes in AWAKE, NREM and REM stages. However, REM sleep is the more affected stage by means of a strong inhibition.
Conclusions: The KPD model developed here describes sleep architecture with and without citalopram treatment, and quantifies the strong REM inhibition effect at multiple dose levels in rats. This population analysis was carried out with the lack of the actual citalopram and n-desmethylcitalopram concentrations. The PD model part of the model (baseline, handling effect) can be also applied for drug effect evaluations of other sleep changing compounds.
References:
[1] N Velez de Mendizabal, K Jackson, B Eastwood, S Swanson, DM Bender, S Lowe, RR Bies. A Population PK Model for Citalopram and Its Major Metabolite, N-desmethyl Citalopram, In Rats. PAGE 22 (2013) Abstr 2694 [www.page-meeting.org/?abstract=2694]
Reference: PAGE 23 () Abstr 3070 [www.page-meeting.org/?abstract=3070]
Poster: Drug/Disease modeling - CNS