A dynamically integrative PKPD model to predict the efficacy of marbofloxacin treatment regimens for bovine Mannheimia hemolytica infection
Ronette Gehring (1), Michael D Apley (1), Jim E Riviere (1)
(1) Institute of Computational Comparative Medicine, Kansas State University
Objectives: To develop a PKPD model that dynamically integrates in vitro and in vivo data, specifically the pharmacokinetics of marbofloxacin in cattle with the in vitro effect of varying concentrations of marbofloxacin on Mannheimia hemolytica, to predict the efficacy of different clinically feasible dosage regimens.
Methods: A Hill equation was fit to published time-kill data for marbofloxacin and bovine isolates of Mannheimia hemolytica [1] [2]. Marbofloxacin plasma concentrations were predicted using a published three compartment model in calves [3]. The predicted concentration served as input for the Hill equation to predict fluctuations in bacterial growth as a result of exposure to changing marbolfoxacin concentrations over time. The sensitivity of the bacterial population to marbofloxacin was varied to an MIC that was 8 fold higher than was used to initially parameterize the Hill equation. Simulations for 5 different clinically feasible dosing regimens were done using ACSLXtreme (Aegis Technologies, Huntsville, AL). Bacterial population sizes at 24 hours after the final dose were compared.
Results: All dosage regimens were equally effective in decreasing populations of highly sensitivie bacteria. Those that administered higher doses less frequently remained effective as the bacteria became more resistant, whereas dosage regimens that administered lower doses more frequently became less effective. None of the dosage regimens were effective once sensitivity of the bacteria to marbofloxacin had decrease to a six fold higher MIC from the original population used to parameterize the Hill equation.
Conclusions: This integrative PKPD model offers an economical tool to predict to effective dosage regimens that may then be validated with carefully designed clinical trials. Variability of the drug's pharmacokinetics within the target population can easily be incorporated into the simulations using this model. This has the potential to decrease the cost of drug development, as well as identifying breakpoints for resistant isolates.
References:
[1] Roeges RR, Wiuff C, Zappala RM, Garner KN, Baquero F and Levin BR (2004) Pharmacodynamic functions: A multiparameter approach to the design of antibiotic treatment regimens. Antimicrobial Agents and Chemotherapy, 48 (10): 3670-6
[2] Sidhu PK, Landoni MF, Aliabadi MH, Toutain PL and Lees P (2011) Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves. Journal of Veterinary Pharmacology and Therapeutics, 34 (4): 376-87
[3] Aliabadi FS and Lees P (2002) Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. Journal of Veterinary Pharmacology and Therapeutics, 25 (3): 161-74