Pharmacokinetics And Pharmacodynamics Of Moxifloxacin In Intra-abdominal Infected Rats And The Extrapolation Between Species

OBJECTIVE: 1. To investigate the pharmacokinetics and pharmcodynamics of moxifloxacin in intra–abdominal infected rats induced by Escherichia coli.2. To develop a physiologically based pharmacokinetic(PBPK) model in intra–abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues between different species and people of different ages to promote clinical rational drug use.METHODS: 1. Methodological study of the determination of moxifloxacin concentrations in rat plasma: high–performance liquid chromatography(HPLC);The chromatography was done at room temperature on a reversed–phase Kromasil C18column(150×4.6 mm, 5μm) with an injection volume of 20 μL. The mobile phase consisted of 0.1%(v/v) triethylamine, at p H 2.8(adjusted with dilute phosphoric acid)and methanol(38:62 v/v) at a flow rate of 1 m L?min-1. Detection was performed at296 nm using UV detector. Sensitivity: 0.005AUFS; internal standard: ciprofloxacin.2. Pharmacokinetics and pharmacodynamics research of moxifloxacin in intra –abdominal infected rats: Intra–abdominal infection model were induced by intraperitoneal injection of clinical isolated E. coli 6857 bacteria liquid(2×109CFU/m L) through left lower abdomen. 24 rats were randomly divided into treatment and control groups. Rats intreatment group were injected with a single dose of 40mg/kg body weight of moxifloxacin 2h after infection and the control group were given normal saline of the same quantity. Blood samples were collected from the inter canthus at 0h, 4h, 8h, 24 h for bacteria counting. The concentrations of moxifloxacin were determined by HPLC at 5min、10min、20min、30min、1h、2h、4h 、 8h 、 24 h after treatment. Then calculate the PK/PD parameter of moxifloxacin against E. coliand draw the 24 h – killing curve of moxifloxacin in rats.3. The development of the rat PBPK model and extrapolation between species: The rat PBPK model was built based on the physicochemical properties, in vitro data and delivery information of moxifloxacin and validated by the observed concentration data. Extrapolate the rat PBPK model to human and validate the human PBPK model.Then, extrapolate the model to elderly male and female to predict thepharmacokinetics and tissue distribution of moxifloxacin in those populations.RESULTS: 1. Methodological study of the determination of moxifloxacin concentrations in rat plasma: Under the conditions of our study, rentention times of moxifloxacin and the internal standard were 21 min and 7.8 min, respectively.The lower–limit of quantification was 0.2μg/m Lwith the equation of linear regression: y =0.29 x + 0.0497(R2 = 0.9995). The linear range was 0.2~20.0 μg·m L-1.The mean recovery of absolute and method were 67.27 % and 99.37 %, respectively. And the method showed good accuracy(RSD < 10 %), repeatability(RSD = 1.22 %) and stability(RSD<5.6%).2. Pharmacokinetics and pharmacodynamics research of moxifloxacin in intra –abdominal infected rats: In the plasma concentration versus time profile of moxifloxcinin rats, Cmax、t1/2、AUC0-24、CL and V were 11.151 μg·m L-1、2.936 h、28.913 h·μg·m L-1 、 0.287 L ·h-1and 1.709 L, respectively. The final Cmax/MIC and AUC/MIC were 185.85 and 481.88 h. The 24 h – killing curve showed that moxifloxacin had good effect on E. coli and almost all bateria were killed 24 h after treatment.3. The development of the rat PBPK model and extrapolation between species: A PBPK model was developed in rat with intra–abdominal infection. The validation result showed that the predicted concentration versus time profile was reasonably consistent(<2–fold error) with the observed values, which suggested that the model was reliable. Based on the validated rat model, the extrapolated PBPKmodel in human was successful and have a good fit. The final PBPK model indicated that there was no significant difference between the concentrations of moxifloxacin in different ages of human. The PK results showed that moxifloxacin penetrated well into the human body, and its concentrations in most of the tissues were higher than that in blood. The tissue to plasma concentration ratios in redmarrow, kidney, liver, spleen,heart, skin, muscle and lung were 2.72, 2.20, 2.11, 1.85, 1.74, 1.62, 1.60 and 1.34,respectively.CONCLUSION: The HPLC method had high specificity, sensitivity and reproducibility which can be used to determine the moxifloxacin concentration in rat plasma for clinical and pharmacokinetic research. Moxifloacin had good effect onintra–abdominal infected rats induced by clinical isolated E. coli. Dosage adjustment of moxifloxacin was not needed in diferent ages, as there was no difference in the PK parameters. The tissue distribution prediction indicated that moxifloxacin was expected to be useful in treating osteomyelitis, endocarditis and intra – abdominal infection and drug monitoring would be required to assess possible advers drug effect caused by the high concentrations.