Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB

Abstract

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Fig 1. Escitalopram plasma concentration over time after IV injection of 0.83 mg/kg escitalopram.

This IV injection was given 6 hours after the last gift of the preliminary oral treatment (0.83 mg/kg, 3 administrations/day, 4 days).

Fig 2. Time-activity curves in basal ganglia and reference region after IV injection of [¹¹C]DASB at baseline levels and after a four day oral treatment period with escitalopram (2 mg/kg/day divided over 3 administrations).

Fig 3. Coregistration of MRI and PET, at baseline levels and after a four day oral treatment period with 2 mg/kg/day escitalopram.

The SUV_bw parameter is presented for each voxel on a summed PET-image between 40 and 60 minutes after IV injection of [¹¹C]DASB. Regions of interest delineated on MRI: BG: basal ganglia, Ce: cerebellar cortex (vermis excluded), Co: colliculi, Hi: hippocampus, Th: thalamus, RN: brainstem region containing the raphe nuclei.

Fig 4. Relationship between the dose of escitalopram and the SERT-occupancy measured in the basal ganglia.

R² represents the nonlinear regression fit of the hyperbola; K_D^app represents the required dose to occupy 50% of the SERT sites. * represents the excluded experimental data point for the fitting.