Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2‐adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate...

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Bibliographic Details
Published in:Journal of veterinary pharmacology and therapeutics 2015-02, Vol.38 (1), p.24-34
Main Authors: Grimsrud, K. N., Ait-Oudhia, S., Durbin-Johnson, B. P., Rocke, D. M., Mama, K. R., Rezende, M. L., Stanley, S. D., Jusko, W. J.
Format: Article
Language:English
Subjects:
Adrenergic alpha-2 Receptor Antagonists - administration & dosage
Adrenergic alpha-2 Receptor Antagonists - blood
Adrenergic alpha-2 Receptor Antagonists - pharmacokinetics
Adrenergic alpha-2 Receptor Antagonists - pharmacology
Animals
Dexmedetomidine - administration & dosage
Dexmedetomidine - blood
Dexmedetomidine - pharmacokinetics
Dexmedetomidine - pharmacology
Dose-Response Relationship, Drug
Female
Horses - blood
Horses - metabolism
Imidazoles - administration & dosage
Imidazoles - blood
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Male
Medetomidine - administration & dosage
Medetomidine - blood
Medetomidine - pharmacokinetics
Medetomidine - pharmacology
Models, Biological
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Summary:The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2‐adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half‐maximal effect (IC50) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.
ISSN:0140-7783
1365-2885
DOI:10.1111/jvp.12139