AUTHOR=Yang Qingwen , Liu Xuesong , Zhang Chenghuan , Yong Kang , Clifton Alancia Carol , Ding Huanzhong , Liu Yun 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01090

DOI=10.3389/fphar.2019.01090

ISSN=1663-9812

ABSTRACT=<p>Gamithromycin is approved for the treatment and prevention of bovine respiratory disease (BRD), which is caused mainly by <italic>Mannheimia haemolytica, Pasteurella multocida, Histophilus somni</italic>, and <italic>Mycoplasma</italic> 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 <italic>P. multocida</italic> and to further define the PK/PD parameter that best correlates with the efficacy of gamithromycin against <italic>P. multocida</italic>. 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 (<italic>f</italic>) 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 (<italic>f</italic> AUC<sub>0–24</sub>) and the peak drug concentration (<italic>f C</italic><sub>max</sub>) 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 <italic>P. multocida</italic> in mice serum was 0.15 μg/ml. Analysis of PK/PD indices using the inhibitory effect <italic>E</italic><sub>max</sub> model indicated a strong correlation (<italic>R</italic><sup>2</sup> = 0.9624) between the <italic>f</italic> AUC<sub>0–24</sub>/MIC ratio and various antibacterial effects. The area under the unbound concentration–time curve over 24 h to MIC (<italic>f</italic> AUC<sub>0–24</sub>/MIC) predicted for bacteriostatic action, 1-log<sub>10</sub> reduction, 2-log<sub>10</sub> reduction, and 3-log<sub>10</sub> reduction were 56.77, 90.18, 143.06, and 239.44 h, respectively. These <italic>in vivo</italic> data may facilitate gamithromycin dosage optimization against <italic>P. multocida</italic> in veterinary medicine.</p>