National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, China.
MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan 430070, China.
Int J Mol Sci. 2022 Mar 28;23(7):3722. doi: 10.3390/ijms23073722.
Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC/MIC and AUC /MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.
模型指导药物开发由于其能够整合数据的变异性和不确定性，因此是药物开发和临床应用的有价值的工具。本研究旨在通过体外药代动力学/药效学（PK/PD）模型确定头孢噻呋针对 的最佳剂量，并通过生理基于药代动力学/药效学（PBPK/PD）模型验证剂量方案。确定了头孢噻呋在血浆和支气管肺泡灌洗液（BALF）中的药代动力学特征。研究了头孢噻呋对 的 PD 性能。通过建立 PK/PD 模型，确定了 PK/PD 参数和剂量。建立了 PBPK 模型和 PBPK/PD 模型来验证剂量疗效。确定了杀菌作用、杀菌作用和消除作用的 PK/PD 参数 AUC/MIC 分别为 44.02、89.40 和 119.90 h，相应的剂量分别为 0.22、0.46 和 0.64 mg/kg。通过 PBPK 模型模拟 AUC/MIC 和 AUC/MIC，与 PK/PD 参数相比，治疗效果可达到 90%的目标命中率（PTA）。通过 PBPK/PD 模型预测了细菌生长的时间过程，表明 0.46 mg/kg 体重的剂量可以抑制细菌生长并发挥良好的杀菌作用。
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