Optimization and Validation of Dosage Regimen for Ceftiofur against Pasteurella multocida in Swine by Physiological Based Pharmacokinetic-Pharmacodynamic Model

• Published in: International journal of molecular sciences Vol. 23; no. 7; p. 3722
• Main Authors: Mi, Kun, Pu, Shanju, Hou, Yixuan, Sun, Lei, Zhou, Kaixiang, Ma, Wenjin, Xu, Xiangyue, Huo, Meixia, Liu, Zhenli, Xie, Changqing, Qu, Wei, Huang, Lingli
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.03.2022; MDPI
• Subjects: Animals; Anti-Bacterial Agents - therapeutic use; Antibiotics; Body weight; Bronchus; ceftiofur; Cephalosporins - pharmacology; Clinical medicine; Disease; Dosage; dosage regimen; Drug development; Drug dosages; Drug resistance; Hogs; Lavage; mathematical model; Mathematical models; Microbial Sensitivity Tests; Minimum inhibitory concentration; Monte Carlo simulation; Parameters; Pasteurella multocida; Pathogens; PBPK/PD model; Pharmacodynamics; Pharmacokinetics; Pharmacology; Physiology; Plasma; Public health; Swine; PBPK/PD model; mathematical model; ceftiofur; dosage regimen; Pasteurella multocida
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.