Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis

Abstract

Background: Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis.

Results: Inflammation was induced in the radiocarpal joint of six horses by injection of 2 ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3 mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis.

Conclusions: The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.

Keywords: Corticosteroids; Pharmacodynamics; Pharmacokinetics; Quantitative pharmacology.

Fig. 1

Illustration of the sequential approach that was adopted to estimate the PK/PD parameters. The upper row shows the dexamethasone synovial fluid and plasma disposition model (a) and the lower row the pharmacodynamic model (b) describing the LPS challenge and lameness response (R_LL). The post hoc estimates of individual PK parameters were fixed to their post hoc estimate to “drive” the drug-mechanism function (I(C_syn)) acting on production of lameness response induced by the LPS-challenge [25]

Fig. 2

Observed dexamethasone synovial fluid (filled circles) and plasma (open circles) concentrations over time after intra articular administration of dexamethasone sodium phosphate into the LPS-challenged joint

Fig. 3

Observed dexamethasone concentration vs population model predicted dexamethasone concentration (upper row) and observed dexamethasone concentration vs individual model predicted dexamethasone concentration (lower row)

Fig. 4

Conditional weighted residuals (CWRES) over time (left column, a) and CWRES over population model predictions (right column, b) for dexamethasone in plasma (upper row) and synovial fluid (lower row) after treatment with LPS + dexamethasone sodium phosphate administered intra-articularly and in plasma (intermediate row) after treatment with dexamethasone sodium phosphate administered intra-intravenously

Fig. 5

Change in (mean and standard deviation) lameness relative to baseline in six horses challenged with 2 ng lipopolysaccharides in the radiocarpal joint at hour − 2. At hour 0 either saline (filled circles) or dexamethasone (open circles) was injected in the LPS challenged joint. The horses received one dose dexamethasone sodium phosphate each. The doses were 0.01, 0.03, 0.1, 0.3, 1, and 3 mg administered in an injection volume of 2 mL. Upper plot (a): change in minimum head height differences (HD_min) scored objectively. Lower pot (b): change in American Association of Equine Practitioners (AAEP) lameness score

Fig. 6

Observed lameness response (HD_min) vs population model predicted HD_min (upper row) and observed HD_min vs individual model predicted HD_min (lower row) after treatment with either LPS + saline (left column) or LPS + dexamethasone sodium phosphate (right column) administered intra-articularly

Fig. 7

Conditional weighted residuals (CWRES) over time (upper row) for and CWRES versus lameness response (lower row) after treatment with either LPS + saline (left column) or LPS + dexamethasone sodium phosphate (right column) administered intra-articularly