Pharmacokinetics/Pharmacodynamics(PK/PD) Of Tildipirosin In Mice

Plasma, epithelial lining fluid(ELF) and lung pharmacokinetics(PK) of tildipirosin(TIP), as well as the penetration of TIP into ELF and lung in healthy mice were investigated in our study. The lung-infected mice were also used for the PK of TIP in plasma in infected mice against Pasteurella multocida and for the comparision of the PK properties between infected and healthy mice. Multiple dosing regimens were applied for the assessment of the in vivo antibacterial activity of TIP and relationships of pharmacokinetics and pharmacodynamics(PK/PD) in infected mice against Pasteurella multocida. All of these done were for better guidance in clinical application. The main contents and results of this thesis are as follows:Plasma, bronchoalceolar lavage fluid(BALF) and lung tissue were obtained at the predetermined time points in healthy mice after subcutaneous injection administration of various doses. The concentrations of TIP in all samples were determined by liquid chromatography-tandem mass spectrometry(HPLC-MS/MS). Urea nitrogen values of plasma(Uplasma) and BALF(UBALF) were got using urease method. The concentration of TIP in ELF was calculated on the basis of the formula: CELF = CBALF ×Uplasma / UBALF. The PK data were analyzed using non-compartmental modeling in Win Nonlin 5.2.1. The results were as follows: tmax in plasma, ELF and lung were 0.083 h, 0.381±0.238 h and1.125±0.629 h, with the corresponding values of t1/2 were 14.123±1.758 h; 49.494±8.028 h and 33.663±2.802 h, respectively. The ratio of AUCELF/AUCPlasma was 1.23~2.18 and that of AUCLung/AUCPlasma was 20.40~27.74.Plasma pharmacokinetics of TIP in lung-infected mice was carried out after subcutaneous injection administration of various doses, and plasma samples were collected at the same time as that in healthy mice. TIP concentration in plasma was also analyzed by HPLC-MS/MS, together with the same data processing software Win Nonlin 5.2.1.Significance test of the main PK parameters between the infected and healthy mice were also done, showing no significance except Vz/F, CL/F and AUC, of which the former two were significantly higher but the later was lower.Twenty dosage regimens were applied to estimate in vivo efficacy of TIP in infectedmice against Pasteurella multocida. The results showed that the PK/PD parameter AUC24h/MIC played an important role in describing the efficacy of TIP against Pasteurella multocida(r2=0.8154). The sigmoid Emax model was used in simulating the data, and the values of AUC24h/MIC required for a static effect, 0.5-log, 1-log, 1.5-log and 2-log reduction were 23.14 h, 29.31 h, 37.88 h, 51.17 h and 75.76 h, respectively.