Agnieszka Borsuk-De Moor (1), Justyna Warzybok (2) , Agnieszka Bienert (2), Włodzimierz Płotek (3), Katarzyna Czerniak (3), Hanna Billert (3), Agnieszka Klupczyńska (4), Jan Matysiak (4), Edmund Grześkowiak (2), Paweł Wiczling (1)
(1) Department of Biopharmacy and Pharmacodynamics, Medical University of Gdańsk, ul. Hallera 107, 80-416 Gdańsk, Poland, (2) Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznań, Poland, (3) Department of Experimental Anaesthesiology, Poznań University of Medical Sciences, ul. Św. MariiMagdaleny 14, 61-861 Poznań, Poland, (4) Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznań, Poland
Introduction: Dexmedetomidine (DEX) is a relatively new sedative agent with a growing use in the pediatric population. However, limited data exist concerning the influence of age on the pharmacokinetics of DEX and the data regarding age influence on DEX pharmacodynamics is lacking. Studies in laboratory conditions offer decreasing of the error related to the inter-subject variability by developing PK/PD model in laboratory animals with each animal serving as its own control.
Objectives: The aim of this study was to develop population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine in rabbits and investigate the relationship between model parameters and age and weight of rabbits. Another aim was to investigate the linearity of pharmacokinetics of the drug in the examined dose range.
Methods: 18 New Zealand white rabbits were investigated during this prospective, cross-over study. Dexmedetomidine was administered as a single bolus injection in the following doses: 25 µg/kg, 35 µg/kg, 50 µg/kg, 75 µg/kg, 100 µg/kg, 140 µg/kg, 150 µg/kg, 200 µg/kg, 250 µg/kg and 300 µg/kg, with three rabbits per each dose. Specified dose of the drug was given to the same animal at 3 subsequent stages of age development at median ages of 44 (n=14), 79 (n=12) and 192 (n=14) days. To determine dexmedetomidine pharmacokinetics, 7 blood samples were taken from each animal. Pedal withdrawal reflex was the PD response measured to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis.
Results: Dexmedetomidine pharmacokinetics was described by two-compartment model. Interindividual variability was estimated for CL, V1 and V2. Since the animals were examined at different occasions, the inclusion of interoccasion variability in individual parameters was tested and estimated for CL in the final model. Pharmacodynamic response was modeled by logistic regression in relation to the apparent drug concentration in the effect compartment (biophase) with interindividual variability estimated for biophase distribution rate constant. Age was identified as a significant covariate affecting the clearance. The typical value of elimination clearance was 0.057 L/min and was higher in younger rabbits compared to older animals. The estimated volumes of distribution of the central and peripheral compartment were 0.53 L and 0.89 L, respectively, and the estimated intercompartmental clearance was 0.08 L/min. Interindividual and interoccasion variability of parameters were below 36 %. The pharmacokinetics of dexmedetomidine was linear in the examined concentration range. The age-related changes in pharmacodynamics were not detected.
Conclusions: The results suggest that younger rabbits will have lower dexmedetomidine concentrations and shorter duration of anaesthesia for the same doses of dexmedetomidine per kg of body weight than older animals.
Acknowledgements: This study was supported by the Polish National Science Centre grant no. 2015/17/B/NZ7/03032
Reference: PAGE 28 (2019) Abstr 8840 [www.page-meeting.org/?abstract=8840]
Poster: Drug/Disease Modelling - CNS