畜牧兽医学报 ›› 2025, Vol. 56 ›› Issue (8): 4007-4017.doi: 10.11843/j.issn.0366-6964.2025.08.038

• 基础兽医 • 上一篇    下一篇

基于PK/PD模型对甲砜霉素粉在鸡口服给药方案药效再评价

谷日飞1,2(), 张思微1,2(), 赵志杰1,2, 宋伟硕1,2, 张峻铭1,2, 马晓茹1,2, 高嫣珺1,2,*(), 卜仕金1,2,*()   

  1. 1. 扬州大学兽医学院, 扬州 225009
    2. 江苏省动物重要疫病与人兽共患病防控协同创新中心, 扬州 225009
  • 收稿日期:2024-09-29 出版日期:2025-08-23 发布日期:2025-08-28
  • 通讯作者: 高嫣珺,卜仕金 E-mail:grfei926@163.com;1335322522@qq.com;820898490@qq.com;sjbo@yzu.edu.cn
  • 作者简介:谷日飞(2000-),男,山西大同人,硕士生,主要从事兽医药理与毒理学研究,E-mail:grfei926@163.com
    张思微(1998-),女,安徽宿州人,硕士,主要从事兽医药理与毒理学研究,E-mail:1335322522@qq.com
    第一联系人:

    谷日飞与张思微为同等贡献作者

  • 基金资助:
    江苏高校优势学科建设工程资助项目(PAPD)

Effectiveness Revaluation of Thiamphenicol Powder Oral Dosage Regimen in Chickens Based on PK/PD Model

GU Rifei1,2(), ZHANG Siwei1,2(), ZHAO Zhijie1,2, SONG Weishuo1,2, ZHANG Junming1,2, MA Xiaoru1,2, GAO Yanjun1,2,*(), BU Shijin1,2,*()   

  1. 1. College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
    2. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
  • Received:2024-09-29 Online:2025-08-23 Published:2025-08-28
  • Contact: GAO Yanjun, BU Shijin E-mail:grfei926@163.com;1335322522@qq.com;820898490@qq.com;sjbo@yzu.edu.cn

摘要:

通过开展甲砜霉素粉在鸡口服给药的体内药动学试验获得有关药动学参数,结合蒙特卡洛模拟(MCS),评估甲砜霉素粉在鸡临床推荐给药方案的合理性。设静脉注射组(10 mg·kg-1, 按体重计算)和口服低、高剂量组(10、20 mg·kg-1, 按体重计算)3组,预定时间采集血样,采用经验证的鸡血浆中甲砜霉素含量HPLC测定方法检测鸡血浆中甲砜霉素的浓度。拟合甲砜霉素在鸡体内药动学参数,建立甲砜霉素对多杀性巴氏杆菌(Pasteurella multocida)的流行病学临界值(ECOFF),结合甲砜霉素对多杀性巴氏杆菌抑菌、杀菌和清除对应的PK/PD临界值,经MCS获得当前给药方案对多杀性巴氏杆菌不同MIC分布下的达标率(target attainment rate, TAR),进一步优化临床给药方案。结果显示,甲砜霉素10 mg·kg-1(按体重计算)单剂量静注给药后,AUCinf为(14.21±5.69) μg·h·mL-1T1/2Z为(1.85±1.20)h,CL为(803.11±297.78)mL·(kg·h)-1VC为(403.63±93.74)mL·kg-1;甲砜霉素粉按10、20 mg·kg-1(按体重计算)单剂量经口灌服给药后,Cmax分别为(1.70±0.27)μg·mL-1和(3.36±0.98)μg·mL-1Tmax分别为(1.30±0.48)h和(1.50±0.53)h,AUCinf分别为(5.01±0.80)μg·h·mL-1和(12.38±3.21)μg·h·mL-1T1/2Z分别为(2.25±1.03)h和(2.31±1.00)h,口服生物利用度分别为33.84%和43.08%。甲砜霉素粉低、高剂量(10、20 mg·kg-1, 按体重计算)对多杀性巴氏杆菌在ECOFF(2 μg·mL-1)处抑菌、杀菌和清除的达标率分别为26.96%和86.03%、10.77%和58.89%、9.40%和49.62%,均小于90%。计算获得抑菌、杀菌和清除的达标率所需24 h给药量分别为43.1、66.4和78.1 mg·kg-1(按体重计算)。结果表明,甲砜霉素粉当前在鸡的临床推荐给药方案无法实现对多杀性巴氏杆菌全身感染的细菌学治愈,建议有效的24 h给药推荐量为45 mg·kg-1(按体重计算)。

关键词: 甲砜霉素粉, PK/PD, 多杀性巴氏杆菌, 药效再评价

Abstract:

This study aimed to investigate the in vivo pharmacokinetics of thiamphenicol powder in chickens after oral administration. After the pharmacokinetic parameters were obtained, the rationality of the recommended oral dosing regimen of thiamphenicol powder in chickens was revaluated by Monte Carlo simulation (MCS). Three groups were set: thiamphenicol 10 mg·kg-1 BW intravenous injection group, and thiamphenicol powder 10 and 20 mg·kg-1 BW oral gavage groups. Blood samples were collected at a scheduled time and the concentration of thiamphenicol in chicken plasma was determined by a verified HPLC method. The pharmacokinetic parameters of thiamphenicol in chickens were fitted, and the epidemiological cut-off value (ECOFF) of thiamphenicol against Pasteurella multocida was established. Then the PK/PD cut-off values at bacteriostatic, bactericidal, and eradication of thiamphenicol against Pasteurella multocida were used to predicate the target attainment rate (TAR) by MCS. The effective dose was calculated to optimize the clinical dosage regimen. The results showed that AUCinf, T1/2Z, CL and VC were (14.21±5.69) μg·h·mL-1, (1.85±1.20) h, (803.11±297.78) mL·(kg·h)-1, and (403.63±93.74) mL·kg-1, respectively, after intravenous administration of 10 mg·kg-1 BW. After oral administration of 10 and 20 mg·kg-1 BW, the Cmax were (1.70±0.27) μg·mL-1 and (3.36±0.98) μg·mL-1, the Tmax were (1.30±0.48) h and (1.50±0.53) h, the AUCinf were (5.01±0.80) μg·h·mL-1 and (12.38±3.21) μg·h·mL-1, T1/2Z were (2.25±1.03) h and (2.31±1.00) h, and oral bioavailability were 33.84% and 43.08%, respectively. The TAR that bacteriostatic, bactericidal, and eradication of Pasteurella multocida under ECOFF (2 μg·mL-1) by the low and high doses (10 and 20 mg·kg-1 BW) of thiamphenicol powder were 26.96% and 86.03%, 10.77% and 58.89%, 9.40% and 49.62%, respectively, all of which were less than 90%. The 24 h dosage for bacteriostatic, bactericidal, and eradication was calculated as 43.1, 66.4 and 78.1 mg·kg-1 BW, respectively. These results indicate that the current dosage regimen cannot realize the bacteria cure of chicken Pasteurella multocida infection and that at least 45 mg kg-1 BW is necessary for effectiveness.

Key words: thiamphenicol powder, PK/PD, Pasteurella multocida, efficacy revaluation

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