The dose regimen formulation of tilmicosin against Lawsonia intracellularis in pigs by pharmacokinetic-pharmacodynamic (PK-PD) model. (October 2020)

• Record Type: Journal Article
• Authors: Luo, Wanhe; Qin, Hua; Chen, Dongmei; Wu, Mengru; Meng, Kuiyu; Zhang, Aoxue; Pan, Yunahu; Qu, Wei; Xie, Shuyu
• Is Part Of: Microbial pathogenesis. Volume 147(2020)
• Publication Date: 2020-10
• Subjects: L. intracellularis -- Pharmacokinetic-pharmacodynamic (PK-PD) model -- Pig -- Tilmicosin -- Dosage regimen; Pathogenic microorganisms -- Periodicals; Pathology, Molecular -- Periodicals; Communicable Diseases -- microbiology -- Periodicals; Communicable Diseases -- parasitology -- Periodicals; Micro-organismes pathogènes -- Périodiques; Pathologie moléculaire -- Périodiques; Electronic journals; 616.9041
• DOI: 10.1016/j.micpath.2020.104389
• Languages: English
• ISSNs: 0882-4010

Abstract

Abstract: In this study, the rational dose regimens of tilmicosin against Lawsonia intracellularis ( L. intracellularis ) were studied using pharmacokinetic-pharmacodynamic (PK-PD) model approach to provide a maximal efficacy. The healthy and infected pigs were orally administrated the tilmicosin premix at a single dose of 10 mg/kg, and then the plasma and ileum content were collected at different time points. The time to peak (Tmax ), the peak concentration (Cmax ), the area under concentration time curve (AUC0–24h ), the apparent volume of distribution by bioavailability (V/F), the body clearance rate by bioavailability (CL/F) and the mean residence time (MRT) of tilmicosin premix for plasma were 2.00 h, 1.08 ± 0.04 μg/mL, 9.61 ± 1.47 μg h/mL, 34.43 ± 1.02 L/kg, 0.71 ± 0.03 L/h/kg and 15.03 ± 0.04 h in healthy pigs, and 2.00 h, 0.99 ± 0.03 μg/mL, 9.30 ± 1.43 μg h/mL, 58.59 ± 1.81 L/kg, 0.44 ± 0.02 L/h/kg and 15.75 ± 0.03 h in infected pigs, respectively. The Tmax, Cmax, AUC0–24h, V/F, CL/F and MRT of tilmicosin premix for ileum content were 2.00 h, 3.78 ± 0.03 μg/mL, 20.41 ± 1.64 μg h/mL, 11.29 ± 0.97 L/kg, 0.44 ± 0.02 L/h/kg and 11.29 ± 0.09 h in healthy pigs, and 2.00 h, 3.41 ± 0.06 μg/mL, 22.65 ± 1.32 μg h/mL, 8.16 ± 1.51 L/kg, 0.41 ± 0.01 L/h/kg and 11.44 ± 0.05 h in infected pigs, respectively. Based on the intracellular minimum inhibitory concentration (MIC) of L. intracellularis isolate was 2 μg/mL, the results of the mutant prevention concentration (MPC), the post-antibiotic effect (PAE) and time-killing curves all showed strong concentration-dependenttendencies. Integrating the in vivo pharmacokinetic data of infected pigs and ex vivo pharmacodynamic data using the sigmoid Emax (Hill) equation to obtain the ileum content AUC0–24h /MIC values of 6.87, 26.80, and 36.02 h to achieve the bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria, respectively. Based on these results, a dosage regimen of daily 14.39 mg/kg for 3 d could be sufficient in the treatment of L. intracellularis . This study will provide a guidance of dosage regimen formulation for drug against animal intracellular bacterial infections. Highlights: The rational dose regimens of tilmicosin against L.intracellularis in pigs were studied using PK-PD model for the first time. The MPC, tPAE and time-killing curves of L.intracellularis were studied for the first time and the results showed strong concentration-dependenttendencies. It will be provide a guidance of dosage regimen formulation for drug against the animal intracellular bacterial infections.