Meta-Analysis and Physiologically-Based Modeling of the Pharmacokinetics and Pharmacodynamics of Dexamethasone in Horses.

Abstract

Purpose: Dexamethasone (DEX) is widely used in equine practice for its potent anti-inflammatory effects and diverse studies have examined its pharmacology in horses. We integrated all available pharmacokinetic (PK) and pharmacodynamic (PD) data from 12 studies to quantify DEX disposition and endocrine effects in horses.

Methods: DEX concentrations in blood, urine and synovial fluid, plus cortisol (CTS) and glucose (GLU) in plasma, following various administration routes (intravenous (IV), intramuscular (IM), intra-articular, oral) were available from original studies or digitized from literature. A minimal physiologically-based PK model and linked indirect response PD models were applied.

Results: The mean clearance of DEX was 344 mL/h/kg via hepatic metabolism (98%) and renal excretion (2%). Due to nonlinear tissue binding, DEX generally exhibited a prolonged terminal phase in plasma, maintaining concentrations above a designated plasma threshold of 5 pg/mL for 67 h following 0.05 mg/kg IV dose. Dosing input parameters of DEX varied markedly across dosing routes and prodrug formulations (alcohol, isonicotinate, phosphate), with bioavailability ranging 37 ~ 100%. Oral and pro-drug doses produced rapid absorption, except for IM DEX-isonicotinate that exhibited slow (flip-flop) availability. Adrenal suppression with an IC₅₀ of 0.038 ng/mL and plasma GLU increases with an EC₅₀ of 0.79 ng/mL were observed that commonly persisted for 2 ~ 4 days after single dose.

Conclusions: This meta-analysis utilized a mechanistic and physiologically-based modeling framework to provide global perspectives that may promote the rational use of DEX in equine medicine and support evidence-based regulatory decisions.