Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations

Abstract

Background: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine-treated horses.

Objective: To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation.

Study design: Experimental study.

Methods: Drug plasma and urine concentrations following single intravenous administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 hours for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the international screening limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/mL, urine; 100 ng/mL).

Results: For a regimen of 1.1 mg/kg BW q 24 hours, the IPC and IUC values were 2.0 and 73.0 ng/mL respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 hours after a single 1.1 mg/kg dose administration, 149 and 199 hours after multiple doses over 5 days at either 24- or 12-hour intervals respectively. Corresponding detection times in urine were 46, 68 and 104 hours respectively.

Main limitation: Only female horses were investigated.

Conclusions: Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL.

Keywords: doping; horse; irrelevant plasma concentration; irrelevant urine concentration; medication control.

FIGURE 1

Semilogarithmic spaghetti plots of flunixin disposition curves in plasma and urine after single‐dose administration of 1.1 mg/kg BW flunixin in 10 horses and q 24 h multiple administrations in 10 horses. Solid circles indicate flunixin concentrations in plasma, open circles indicate flunixin concentrations in urine

FIGURE 2

Logarithmic plots of observed flunixin concentrations in plasma (top) and urine (bottom) vs population (PRED) (left plots) and individual predictions (IPRED) (right plots)

FIGURE 3

Conditional weighted residuals (CWRES) vs time plot for plasma (left) and urine (right). Values of CWRES should be approximately N (0, 1) and hence concentrated between y = −2 and y = +2. Inspection of the figure indicates that data were evenly distributed about zero and that the trends (as given by the blue line and the red line with its negative reflection) did not show any fanning, thus indicating no bias in the structural model

FIGURE 4

Visual predictive check of observations vs time after dose in plasma (left) and urine (right) in the case of a single dose of 1.1 mg/kg BW and 1.1 mg/kg BW q 24 h multiple administration. The observed and predicted 10th and 90th percentiles are indicated via solid red and black lines respectively. The observed and predicted 50th percentiles (median) are indicated via red and black broken lines respectively. Blue dots represent individual raw data