Ex vivo pharmacokinetic/pharmacodynamic relationship of valnemulin against Clostridium perfringens in plasma, the small intestinal and caecal contents of rabbits

Abstract

The pharmacokinetic (PK) and ex vivo pharmacodynamic (PD) of valnemulin against Clostridium perfringens were investigated in plasma, the small intestinal and caecal contents of rabbits following intravenous (IV) or oral administration at 3 mg/kg bodyweight (BW). The postantibiotic effect (PAE) and postantibiotic sub-MIC effect (PA-SME) of valnemulin against C. perfringens ATCC13124 were also determined. The time-kill curves were established in vitro and ex vivo to evaluate the antibacterial activity of valnemulin against C. perfringens. The elimination half-lives (T1/2λz) of valnemulin in the jejunal fluids (7.82 h) or caecal contents (14.8 h) of rabbits was significantly longer than that in plasma (2.94 h). The MIC values of valnemulin against C. perfringens ATCC13124 were both 0.063 μg/mL in the artificial medium and jejunal fluids. The PAEs of valnemulin against C. perfringens were 2.9 h (1 × MIC) and 5.03 h (4 × MIC), and the PA-SMEs ranged from 7.9 h to 11.1 h. Valnemulin exhibited rapid, time-dependent killing feature, and the ex vivo dose-response profile was closely fitted to sigmoid Emax model (r(2) = 0.9985). The surrogate index of AUC24 h/MIC ratios required to achieve the bactericidal and virtual bacterial elimination effects were 57.5 and 90.1 h, respectively. Accordingly, the calculated daily dosage regimens of valnemulin for the bactericidal activity (1.96 mg/kg) and bacterial elimination (3.08 mg/kg) would be therapeutically effective in rabbits against C. perfringens with MIC ≤0.5 μg/mL.

Keywords: Clostridium perfringens; PK/PD modeling; Rabbit; Valnemulin.