Rational determination of cefazolin dosage regimen in horses based on pharmacokinetics/pharmacodynamics principles and Monte Carlo simulations.

This research investigated the best dosage regimen of a drug called cefazolin for horses, using a method that combined pharmacokinetics, pharmacodynamics, and Monte Carlo simulations. The findings identified an effective dosage regimen of 5 mg/kg twice a day administered intramuscularly, which proved successful in controlling two specific types of bacteria.

Methodology

• The study conducted a pharmacokinetics/pharmacodynamics (PK/PD) approach to find the optimal dosage regimen for cefazolin (CEZ) in horses.
• Researchers used intramuscular (IM) administration of CEZ in seven horses, each receiving a single IM or intravenous (IV) dose of CEZ of 5 mg/kg bodyweight. This followed a crossover design protocol where each horse in the experiment received both treatments, but in different orders.
• Plasma concentrations of CEZ were measured using a technique known as LC-MS/MS (liquid chromatography tandem mass spectrometry), a highly sensitive and specific method for measuring drugs and metabolites in biological samples.
• The data obtained from these seven horses, together with data from a previous study involving six other horses, were modelled using NonLinear Mixed-Effect modelling.
• The researchers used Monte Carlo simulations with these models to establish a rational dosage regimen. Monte Carlo simulation is a computational algorithm that relies on repeated random sampling to obtain numerical results; it allows predicting the impact of risk and uncertainty in prediction and forecasting models.

Results and Conclusion

• The targeted successful outcome, expressed as a 90% Probability of Target Attainment (PTA), was a free plasma concentration exceeding the minimum inhibitory concentration (MIC) for 40% of the dosing interval, ensuring that the drug concentration in the body is sufficient to treat the infection most of the time.
• The typical half-life of absorption and bioavailability after IM administration were determined to be 1.25 hours and 96.8% respectively. ‘Bioavailability’ refers to the fraction of a dose which reaches the circulation and is available to have an effect.
• The researchers concluded that a CEZ dosage regimen of 5 mg/kg body weight every 12 hours administered via the IM route was effective at controlling both Streptococcus zooepidemicus and Staphylococcus aureus, two types of bacteria found in horses.
• The study emphasised that the intramuscular route of administration should be favoured by clinicians for its efficiency and convenience. In particular, it was found that the duration of effective concentration (the time for which the drug concentration in the plasma remains above the MIC) using this dosage regimen was significantly longer when given IM compared to IV.