制定盐酸头孢噻呋油混悬注射液治疗猪感染的合理剂量方案的药代动力学-药效学（PK-PD）模型。

Formulation of a rational dosage regimen of ceftiofur hydrochloride oily suspension by pharmacokinetic-pharmacodynamic (PK-PD) model for treatment of swine infection.

机构信息

National Reference Laboratory of Veterinary Drug Residues (HZAU) and MARA Key Laboratory for Detection of Veterinary Drug Residues, Wuhan 430070, China.

College of Animal Science and Technology-College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.

出版信息

J Vet Sci. 2021 Nov;22(6):e41. doi: 10.4142/jvs.2021.22.e41.

DOI:10.4142/jvs.2021.22.e41

PMID:34854264

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8636649/

Abstract

BACKGROUND

Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine infections, while the irrational dose has not been formulated.

OBJECTIVES

The rational dose regimens of CEF oily suspension against were systematically studied using a pharmacokinetic-pharmacodynamic model method.

METHODS

The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC/MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating pharmacokinetic data of the infected pigs and pharmacodynamic data using the sigmoid E (Hill) equation. The dose was calculated based on the AUC/MIC values for bacteriostatic action, bactericidal action, and bacterial elimination.

RESULTS

The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 µg/mL, 811.99 ± 54.70 μg·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 µg/mL, 735.85 ± 26.20 μg·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against was 0.25 µg/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC/MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity.

CONCLUSIONS

A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against infections.

摘要

背景

我们之前制备的盐酸头孢噻呋（CEF）油性混悬液显示出在控制猪感染方面有广泛的应用潜力，但其不合理的剂量尚未确定。

目的

采用药代动力学-药效学模型方法系统研究盐酸头孢噻呋油性混悬液的合理剂量方案，以治疗。

方法

健康和感染猪单剂量肌肉注射 5mg/kg 的盐酸头孢噻呋油性混悬液，然后在不同时间采集血浆和肺上皮衬液（PELF）。测定最小抑菌浓度（MIC）、最小杀菌浓度、突变预防浓度（MPC）、抗生素后效应（PAE）和时程杀灭曲线。随后，通过整合感染猪的药代动力学数据和药效学数据，使用 S 形 E（Hill）方程获得 PELF 中去呋喃甲酰头孢噻呋（DFC）的 MIC 曲线下面积（AUC/MIC）值。根据 AUC/MIC 值计算出抑菌作用、杀菌作用和细菌消除的剂量。

结果

PELF 中 DFC 的达峰浓度、浓度-时间曲线下面积和达峰时间分别为健康猪 24.76±0.92µg/mL、811.99±54.70µg·h/mL 和 8.00h，感染猪 33.04±0.99µg/mL、735.85±26.20µg·h/mL 和 8.00h。PELF 中 DFC 的 MIC 对为 0.25µg/mL。通过 MPC、PAE 和时程杀灭曲线测定，其具有很强的浓度依赖性活性。PELF 中 DFC 的 AUC/MIC 值对抑菌活性、杀菌活性和虚拟消除细菌分别为 6.54h、9.69h 和 11.49h。因此，每 72 小时 1.94mg/kg 的剂量方案足以达到杀菌活性。