How to extrapolate a withdrawal time from an EHSLC published detection time: a Monte Carlo simulation appraisal.

The research study employs Monte Carlo simulations to investigate how veterinarians can confidently establish appropriate withdrawal times (WTs) for horses who have received legitimate medication treatments, based on published detection times (DTs). The uncertainty factors allowing for sufficient ‘safety spans’ are determined by examining factors influencing DTs, such as pharmacokinetic parameter variabilities and drug sensitivity.

Methodology

The research adopts a Monte Carlo simulation approach to determine potential variability and uncertainty in withdrawal times. This is a computational method that relies on repeated random sampling to obtain numerical results. Two main cases considered were:

• Low variability of pharmacokinetic parameters (CV=20%) involving the use of an uncertainty span of about 40% to transform a mean DT into a WT, covering 90% of the horse population.
• High variability of drugs (CV=40%), where an uncertainty factor of about 2.1-2.2 should be selected, essentially meaning the WT should be twice the DT.

A sensitivity analysis was also conducted to measure the impact of different factors of variability on a final WT.

Findings

Research showed that parameters controlling the terminal half-life of drug disposition have a substantial influence on the DT. Meanwhile, parameters controlling the urinary or plasma concentrations, which include the administered dosage, urine-to-plasma ratio, and bioavailability, have a minimal effect on the DT. These findings indicate that any uncertainties are mainly biological and not easily reduced by managerial measures.

Implications

The study found that when the European Horserace Scientific Liaison Committee (EHSLC) used the currently-standard protocol of six horses, half the trials resulted in a proposed DT that is equal to or exceeds the population’s 90th percentile. However, increasing the number of test horses to eight or ten improves the probability to 85% and 90% respectively. Consequently, veterinarians can derive safer and more reliable WTs by adopting a tailored approach based on published DTs and considering the pharmacokinetic variability of a drug in individual horses.