Pharmacokinetics of remimazolam, midazolam and diazepam in sheep

Kate Burbery; Robert J Brosnan; Alessia Cenani; Marcela Machado; Heather K Knych

doi:10.1016/j.vaa.2024.12.007

Pharmacokinetics of remimazolam, midazolam and diazepam in sheep

Vet Anaesth Analg. 2024 Dec 29:S1467-2987(24)00419-7. doi: 10.1016/j.vaa.2024.12.007. Online ahead of print.

Authors

Kate Burbery¹, Robert J Brosnan², Alessia Cenani³, Marcela Machado³, Heather K Knych⁴

Affiliations

¹ William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, USA.
² Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA. Electronic address: rjbrosnan@ucdavis.edu.
³ Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
⁴ Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; Kenneth L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.

PMID: 39848882
DOI: 10.1016/j.vaa.2024.12.007

Abstract

Objective: To model pharmacokinetics of three benzodiazepines and their metabolites in sheep.

Study design: A nonblinded, prospective, experimental study.

Animals: A group of six adult Hampshire-Suffolk cross-bred sheep (three females, three castrated males), 73 ± 3 kg (mean ± standard deviation).

Methods: Remimazolam, midazolam and diazepam were coadministered as an intravenous (IV) bolus to each sheep, and blood was sampled at 18 time points over 10 hours. HPLC-MS/MS was used to simultaneously measure plasma concentrations of the parent benzodiazepines (metabolites) for remimazolam (CNS 7054), midazolam (α-hydroxymidazolam) and diazepam (nordiazepam, temazepam, oxazepam). Concentrations over time for each compound were fit to noncompartmental models using commercial software. Calculated pharmacokinetic parameters were compared using either repeated-measures anova if normally distributed or Wilcoxon signed-rank tests if not. Differences between agents were significant when p < 0.05 after adjustments for multiple comparisons.

Results: Remimazolam was undetectable in the plasma of all sheep by 3 hours, whereas midazolam and diazepam concentrations were still quantifiable 10 hours after injection. Median (range) clearance rate from plasma was 103 (61-256), 22 (9.6-37) and 38 (20-46) mL kg^-1 minute^-1 for remimazolam, midazolam and diazepam, respectively. Median (range) terminal elimination half-time was 9.8 (4.6-15), 113 (90-271) and 246 (170-624) minutes for remimazolam, midazolam and diazepam, respectively. Except for temazepam, terminal elimination half-times were generally longer for metabolites than for their parent drug.

Conclusions and clinical relevance: Remimazolam elimination is significantly faster than either midazolam or diazepam. The rapid pharmacokinetics of remimazolam may be particularly useful to facilitate fast recovery from sedation and minimize drug residue exposures in food-producing animals.

Keywords: CNS-7056; benzodiazepine; ovine.