Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of danofloxacin in sheep biological fluids

Abstract

The fluoroquinolone antimicrobial drug danofloxacin was administered to sheep intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1.25 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of danofloxacin in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were established by using a tissue cage model. The in vitro and ex vivo activities of danofloxacin in serum, exudate, and transudate against a pathogenic strain of Mannheimia haemolytica were established. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 60.5, 85.6, and 45.7 h, respectively, after i.v. dosing and 55.9, 77.9, and 49.1 h, respectively, after i.m. dosing. After i.m. dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 10.8, 3.0, and 1.6, respectively. The ex vivo growth inhibition data after i.m. dosing were fitted to the inhibitory sigmoid E(max) equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.8, 20.2, and 28.7 h, and slightly higher values were obtained for transudate and exudate. It is proposed that use of these data might provide a novel approach to the rational design of dosage schedules.

FIG. 1.

(a) Semilogarithmic plots of the concentrations of danofloxacin in serum (•), exudate (▪), and transudate (▴) after i.v. (a) and i.m. (b) administration at a dose of 1.25 mg/kg. Values are means ± SDs (n = 6).

FIG. 1.

(a) Semilogarithmic plots of the concentrations of danofloxacin in serum (•), exudate (▪), and transudate (▴) after i.v. (a) and i.m. (b) administration at a dose of 1.25 mg/kg. Values are means ± SDs (n = 6).

FIG. 2.

Ex vivo antibacterial activity of danofloxacin (plots of log₁₀ CFU per milliliter versus time) against M. haemolytica W629 in serum (a), exudate (b), and transudate (c) after i.m. administration at a dose of 1.25 mg/kg. Values are means (n = 6). SD bars are excluded for clarity. Samples were harvested at predetermined times between 0 and 48 h. Data for samples collected at 30 and 36 h are not shown. Cont., control serum containing no danofloxacin.

FIG. 2.

Ex vivo antibacterial activity of danofloxacin (plots of log₁₀ CFU per milliliter versus time) against M. haemolytica W629 in serum (a), exudate (b), and transudate (c) after i.m. administration at a dose of 1.25 mg/kg. Values are means (n = 6). SD bars are excluded for clarity. Samples were harvested at predetermined times between 0 and 48 h. Data for samples collected at 30 and 36 h are not shown. Cont., control serum containing no danofloxacin.

FIG. 2.

Ex vivo antibacterial activity of danofloxacin (plots of log₁₀ CFU per milliliter versus time) against M. haemolytica W629 in serum (a), exudate (b), and transudate (c) after i.m. administration at a dose of 1.25 mg/kg. Values are means (n = 6). SD bars are excluded for clarity. Samples were harvested at predetermined times between 0 and 48 h. Data for samples collected at 30 and 36 h are not shown. Cont., control serum containing no danofloxacin.

FIG. 3.

Plots of ex vivo AUC₂₄/MIC versus bacterial count (log₁₀ CFU per milliliter) for M. haemolytica W629 in serum (a), exudate (b), and transudate (c). The points represent the values observed for individual animals, and the curve is the line of best fit, based on the sigmoid E_max equation.

FIG. 3.

Plots of ex vivo AUC₂₄/MIC versus bacterial count (log₁₀ CFU per milliliter) for M. haemolytica W629 in serum (a), exudate (b), and transudate (c). The points represent the values observed for individual animals, and the curve is the line of best fit, based on the sigmoid E_max equation.

FIG. 3.

Plots of ex vivo AUC₂₄/MIC versus bacterial count (log₁₀ CFU per milliliter) for M. haemolytica W629 in serum (a), exudate (b), and transudate (c). The points represent the values observed for individual animals, and the curve is the line of best fit, based on the sigmoid E_max equation.