Study Of Antibacterial Activity Of Vertilmicin In Vitro And PK/PD Modeling Application

Vertilmicin is a new molecule entity(NME) with potent activity against gram-negative and positive bacteria in vitro. Up to now, it is still in the stage of clinical development and only several reports have been published with regard to the quantitative analysis of vertilmicin and pharmacokinetic study in animals or humans. The pharmacodynamic of vertilmicin is unknown and the clinical prospect remains uncertain. In this dissertation, in vitro antibacterial activities of vertilmicin was investigated and a reasonable and effective pharmacokinetic(PK)/ pharmacodynamic(PD) model was established to characterize the PD of vertilmicin and predict its clinical efficacy.Minimum inhibitory concentration(MIC) study was performed with four multidrug-resistant pathogenic bacteria and 20 clinical isolates. Based on MIC result, static time-kill curve was determined in three different strains, including Methicillin-sensitive Staphylococcus aureus(MSSA), Methicillin-resistant Staphylococcus aureus(MRSA) and Pseudomonas aeruginosa(PA), and stability of vertilmicin was tested using liquid chromatography-tandem mass spectrometry(LC/MS/MS) for 24 hours simultaneously. After correction for drug degradation, a one-compartment PD model was established using the NONMRM VI program. The stability of the model and the precision of the parameter estimates were evaluated by nonparametric bootstrap analysis and visual predictive check(VPC). In addition, Dynamic kill curve experiment was carried out within 24 hours in view of the PK data extracted from the previous study. Finally, a mechanism-based PK/PD model of antibacterial activity of vertilmicin was established. The model provided valuable prediction for the antibacterial activity of vertilmicin in the clinical practice, and its applicability was successfully confirmed by comparing the predictive values with the observations of dynamic kill curve. Gentamicin was used as reference agent throughout the assay.The MIC result indicated that gentamicin has higher in vitro antibacterial activity than vertilmicin. However, the static and dynamic time-kill curves showed in general the efficacy of vertilmicin and gentamicin were similar. The LC/MS/MS data illustrated that although the degradation rate of vertilmicin and gentamicin were very small, vertilmicin was less stable than gentamicin. The study of PD modeling demonstrated that, one-compartment with adaptation factor was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The PD parameter estimated from PD model showed that concentration of vertilmicin necessary to achieve the same killing effect was higher than that of gentamicin. According to the prediction by PK/PD modeling, it is suggested that both vertimicin and gentamicin should be administered once daily. Furthermore, based on bacterial activity, the clinical potency of vertilmicin was lower than that of gentamicin. Above all, it can be concluded that vertilmicin may not have promising future or development value only based on the therapeutic effect. But more toxicity and tolerance studies should be performed to investigate the development potential.