Pharmacokinetics and Pharmacodynamics of Gamithromycin Treatment of Pasteurella multocida in a Murine Lung Infection Model

Qingwen Yang; Xuesong Liu; Chenghuan Zhang; Kang Yong; Alancia Carol Clifton; Huanzhong Ding; Yun Liu

doi:10.3389/fphar.2019.01090

Pharmacokinetics and Pharmacodynamics of Gamithromycin Treatment of Pasteurella multocida in a Murine Lung Infection Model

Front Pharmacol. 2019 Sep 24:10:1090. doi: 10.3389/fphar.2019.01090. eCollection 2019.

Authors

Qingwen Yang^{1

2}, Xuesong Liu¹, Chenghuan Zhang¹, Kang Yong², Alancia Carol Clifton¹, Huanzhong Ding³, Yun Liu¹

Affiliations

¹ Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
² Laboratory of Veterinary Pharmacology, Department of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing, China.
³ Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.

Abstract

Gamithromycin is approved for the treatment and prevention of bovine respiratory disease (BRD), which is caused mainly by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma species. In this study, multiple dosage regimens were administered to the neutropenic mouse lung infection model in order to investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of gamithromycin treatment of P. multocida and to further define the PK/PD parameter that best correlates with the efficacy of gamithromycin against P. multocida. The PK characteristics of gamithromycin were analyzed after a single subcutaneous (s.c.) injection (1, 3, 6, and 9 mg/kg). The concentration-time profiles of unbound (f) gamithromycin in plasma samples were analyzed by non-compartmental analysis. The main PK parameters of gamithromycin for the area under the concentration-time curve from 0 to 24 h (f AUC_0-24) and the peak drug concentration (f C _max) values ranged from 0.86 to 8.42 µg·h/ml and from 0.55 to 5.69 µg/ml, respectively. The PD values were calculated based on multiple s.c. injections over 24 h (1, 3, 6, and 9 mg/kg at 6, 8, 12, and 24 h, respectively; total dosage 1-36 mg/ kg). The minimum inhibitory concentration (MIC) of gamithromycin against P. multocida in mice serum was 0.15 μg/ml. Analysis of PK/PD indices using the inhibitory effect E _max model indicated a strong correlation (R ² = 0.9624) between the f AUC_0-24/MIC ratio and various antibacterial effects. The area under the unbound concentration-time curve over 24 h to MIC (f AUC_0-24/MIC) predicted for bacteriostatic action, 1-log₁₀ reduction, 2-log₁₀ reduction, and 3-log₁₀ reduction were 56.77, 90.18, 143.06, and 239.44 h, respectively. These in vivo data may facilitate gamithromycin dosage optimization against P. multocida in veterinary medicine.

Keywords: Pasteurella multocida; gamithromycin; lung infection model; mice; pharmacokinetic/pharmacodynamic.