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

Wanhe Luo; Hua Qin; Dongmei Chen; Mengru Wu; Kuiyu Meng; Aoxue Zhang; Yunahu Pan; Wei Qu; Shuyu Xie

doi:10.1016/j.micpath.2020.104389

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

Microb Pathog. 2020 Oct:147:104389. doi: 10.1016/j.micpath.2020.104389. Epub 2020 Jul 21.

Authors

Wanhe Luo¹, Hua Qin², Dongmei Chen³, Mengru Wu¹, Kuiyu Meng¹, Aoxue Zhang¹, Yunahu Pan¹, Wei Qu¹, Shuyu Xie⁴

Affiliations

¹ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MARA Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.
² Beijing TEAM Junwei Healthcare Technology Development Co., Ltd., Beijing, 102600, China.
³ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MARA Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China; MARA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
⁴ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MARA Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China. Electronic address: xieshuyu@mail.hzau.edu.cn.

PMID: 32707311
DOI: 10.1016/j.micpath.2020.104389

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 (T_max), the peak concentration (C_max), the area under concentration time curve (AUC_0-24h), 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 T_max, C_max, AUC_0-24h, 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 E_max (Hill) equation to obtain the ileum content AUC_0-24h/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.

Keywords: Dosage regimen; L. intracellularis; Pharmacokinetic-pharmacodynamic (PK-PD) model; Pig; Tilmicosin.

Publication types

Review

MeSH terms

Animals
Anti-Bacterial Agents
Lawsonia Bacteria*
Microbial Sensitivity Tests
Swine
Tylosin / analogs & derivatives
Tylosin / pharmacology

Substances

Anti-Bacterial Agents
tilmicosin
Tylosin