Pharmacokinetic–pharmacodynamic modelling of the antinociceptive effect of a romifidine infusion in standing horses

Abstract

Objective To evaluate the effect of a romifidine infusion on antinociception and sedation, and to investigate its relationship to plasma concentration. Study design Prospective, experimental, non-randomized trial. Animals Ten healthy adult warmblood horses. Methods Romifidine (loading dose: 0.08 mg kg-1 , infusion: 0.03 mg kg-1 hour-1) was administered intravenously (IV) over 120 minutes. Romifidine plasma concentrations were determined by capillary electrophoresis. Sedation quality and nociceptive thresholds were evaluated at regular time points before, during and after romifidine administration. The nociceptive RIII reflex was elicited by electrical stimulation at the thoracic limb using a dedicated threshold tracking algorithm and recorded by electromyography at the deltoid muscle. A pharmacokinetic-pharmacodynamic model was established and correlation between romifidine plasma concentration and main output variables tested. Results A two compartmental model best described the romifidine pharmacokinetic profile. The nociceptive thresholds increased compared to baseline in all horses from 10 to 146 minutes after romifidine administration (p < 0.05). Peak effect reached 5.7 ± 2.3 times the baseline threshold. The effect/concentration relationship followed a counterclockwise hysteresis loop. The mean plasma concentration was weakly correlated to nociceptive thresholds (p < 0.01,  = 0.392). The sedative effects were significant until 160 minutes but variable, not correlated to plasma concentration (p = 0.067), and weakly correlated to nociceptive thresholds (p < 0.01,  = 0.33).

Effect of Medetomidine, Dexmedetomidine, and Their Reversal with Atipamezole on the Nociceptive Withdrawal Reflex in Beagles

“…To ease comparison between animals and treatments, the mean baseline NWR threshold was calculated over the 5 min immediately preceding drug administration. The mean relative NWR threshold (absolute threshold divided by its baseline) [ 32 ] was then calculated for every minute after T 0 .…”

Antinociceptive effects of levomethadone in standing horses sedated with romifidine

“…This prospective, randomized, masked crossover experimental study was approved by the local Committee for Animal Experiments (Permission number: BE 8/17). It involved eight adult warmblood horses and was part of a parallel trial investigating the antinociceptive effects of a romifidine CRI (Diez Bernal et al 2019). Government owned horses were recruited from the National Equine Centre and informed consent was provided.…”

“…This method was a modification of assays described for the enantioselective determination of ketamine and its metabolites (Theurillat et al 2016) and methadone and its main metabolite (Theurillat et al 2019) in plasma. In order to be able to monitor romifidine, methadone and its main metabolite in one assay, the amount of highly sulfated γ-cyclodextrin in the pH 3.0 running buffer had to be lowered to 0.14 % (Diez Bernal et al 2019).…”

“…Based on measured plasma concentrations for romifidine (Diez Bernal et al 2019) and levomethadone, a pharmacokinetic model was performed using a commercially available software (Phoenix 64 v.8.0.0.3176 2017, WinNonLin/NLME application; Cetara Inc, USA).…”

“…The best suitable compartmental model was chosen from observation of data fit and diagnostic variables. A PK-PD model had been defined for romifidine alone in the previous study (Diez Bernal et al 2019). The contribution of levomethadone plasma concentrations to the modulation of the NWRT was added to the existing model.…”