Pharmacokinetic-pharmacodynamic integration of danofloxacin in the calf
Pharmacokinetic-pharmacodynamic integration of danofloxacin in the calf
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DOI：
10.1016/s0034-5288(03)00005-5
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发表时间：
2003-06-01
影响因子：
2.4
通讯作者：
Lees, P
中科院分区：
文献类型：
--
作者：
Aliabadi, FS;Lees, P
在一项两期交叉研究中，以 1.25 mg/kg 剂量静脉内 (IV) 和肌内 (IM) 给药后，在犊牛中研究了达氟沙星的药代动力学和药效学，使用组织笼监测血管外分布。静脉给药后，达诺沙星具有较高的分布容积（3.90 L/kg）和相对较快的清除率（1.02 L/kg·h）。 IV和IM给药后的终末半衰期分别为2.65和4.03小时。达氧氟沙星缓慢渗透到组织笼液（漏出液）中并从组织笼液（漏出液）中缓慢清除，消除半衰期（IV 给药后 10.2 小时，IM 给药后 8.9 小时）大于血清。在 Mueller Hinton 肉汤、血清和渗出液中体外建立了达氟沙星对病原体曼海因达溶血性 3575 的抗菌作用。这些数据与体内药代动力学参数、C-max 和 AUC 一起用于确定抗菌活性的替代标志物、C-max/MIC、AUC/MIC 和 T > MIC。 还通过肌内注射达诺沙星给药后在预定时间收集的血清和漏出液样品中离体测定了达诺沙星的抗菌作用。将离体 AUC/MIC 数据与离体细菌计数相结合，确定产生抑菌作用、细菌计数抑制 50%、细菌计数减少 99.9%（杀菌作用）和消除细菌的值。血清的平均值分别为15.9、16.7、18.15和33.5小时，漏出液的平均值分别为15.0、16.34、17.8和30.7小时。血清的 AUC/MIC 效应关系可被视为代表血液和灌注良好组织的浅区室，而漏出液的 AUC/MIC 效应关系可被视为代表灌注不良组织的深部外周区室。提出了一种选择用于临床试验评估的抗菌药物剂量的新方法，使用产生杀菌活性或消除细菌的 AUC/MIC 值以及小牛病原体的 MIC90 值。这种方法有望优化疗效并最大限度地减少耐药性的产生。 (C) 2003 Elsevier Science Ltd. 保留所有权利。
The pharmacokinetics and pharmacodynamics of danofloxacin were studied in calves after intravenous (IV) and intramuscular (IM) administration, at a dose of 1.25 mg/kg in a two period cross-over study, using tissue cages to monitor aspects of extravascular distribution. Danofloxacin had a high volume of distribution (3.90 L/kg) and relatively rapid clearance (1.02 L/kg h) after IV dosing. Terminal half-life was 2.65 and 4.03 h, respectively, after IV and IM administration. Danofloxacin penetrated slowly into and was cleared slowly from tissue cage fluid (transudate), elimination half-life (10.2 h after IV and 8.9 h after IM dosing) being greater than for serum. The antibacterial actions of danofloxacin against the pathogen Mannheinda haemolytica 3575 were established in vitro in Mueller Hinton Broth, serum and transudate. These data were used together with in vivo pharmacokinetic parameters, C-max and AUC to determine the surrogate markers of antimicrobial activity, C-max/MIC, AUC/MIC and T > MIC.The antibacterial actions of danofloxacin were also determined ex vivo in serum and transudate samples harvested at pre-determined times after IM danofloxacin dosing. Ex vivo AUC/MIC data were integrated with ex vivo bacterial count to establish values producing a bacteriostatic action, inhibition of bacterial count by 50%, reduction in bacterial count by 99.9% (bactericidal action) and elimination of bacteria. Mean values were, respectively, 15.9, 16.7, 18.15 and 33.5 h for serum and 15.0, 16.34, 17.8 and 30.7 h for transudate. The AUC/MIC-effect relationships for serum may be regarded as representative of a shallow compartment of blood and well perfused tissues, whilst AUC/MIC-effect relationships for transudate may be considered to represent a deep peripheral compartment of poorly perfused tissues. A novel approach to selecting antimicrobial drug dosage for evaluation in clinical trials, using AUC/MIC values producing either bactericidal activity or elimination of bacteria together with MIC90 values for calf pathogens, is proposed. This approach can be expected to optimise efficacy and minimise the development of resistance. (C) 2003 Elsevier Science Ltd. All rights reserved.