Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

摘要

Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration-time profiles obtained after intramuscular administration of Forcyl (R) in cattle. Animal's status, pre-ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10mg/kg as a single injection. The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC(0-24hr)/MIC (area under the curve/minimum inhibitory concentration) greater than 125hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved. The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1g/ml in pre-ruminants and ruminants and 0.5g/ml in dairy cows.