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

K. N. Grimsrud, S. Ait-Oudhia, B. P. Durbin-Johnson, D. M. Rocke, K. R. Mama, M. L. Rezende, S. D. Stanley, W. J. Jusko

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)24-34
Number of pages11
JournalJournal of Veterinary Pharmacology and Therapeutics
Volume38
Issue number1
DOIs
StatePublished - Feb 1 2015

Bibliographical note

Publisher Copyright:
© 2014 John Wiley & Sons Ltd.

ASJC Scopus subject areas

  • Pharmacology
  • General Veterinary

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