| Part One A Liquid chromatography-tandem mass spectrometry method?LC-MS/MS?was established for the determination of Levetiracetam plasma concentrationObjective:LC-MS/MS for the determination of plasma concentration of LEV in human plasma was established for patients with epilepsy.Methods:LC-MS/MS for determining the plasma concentration of LEV in human plasma was established and validated using a plasma sample.Diazepam was used as internal standard,and the plasma samples were precipitated with acetonitrile.The liquid chromatography-tandem mass spectrometry method was performed on the C18 column.The mobile phase consisted of acetonitrile and H2O.The flow rate was 0.8mL/min and the column temperature was kept at 40?.Transition channels of the protonated molecular?MRM?was m/z171.1-m/z126.1 and m/z285.1-m/z193 for LEV and diazepam.The method was inspected in the aspects of specificity,lower limit of quantification,accuracy,precision,matrix effect,and stability.Results:The linear range of Levetiracetam were from 0.025?g/mL to 2?g/mL(y=5.62×10-3x+2.38×10-2,R2=0.9998)show a good linear relationship.The sample preparation process is simple,and rigorous methodological confirmation is performed at the same time,which can be used for quantitative analysis of LEV.Conclusion:A liquid chromatography-tandem mass spectrometry?LC-MS/MS?method for the determination of levetiracetam in plasma was established.The method has the advantages of high specificity,short analysis time,reasonable linear range,simple sample processing and is suitable for plasma drug concentration monitoring and the study of pharmacokinetics.Part two The study of population pharmacokinetics of levetiracetam in epileptic children in ChinaObjective: To establish the population pharmacokinetics model of levetiracetam?LEV?in epileptic children using a nonlinear mixed effects modeling?NONMEM?approach.And to establish and apply the individualized drug delivery mode based on the model.Methods: A total of 318 samples and relevant information were collected from 298 epileptic children retrospectively,who were taken levetiracetam orally?age from 6 month to16 years?.The population pharmacokinetics model of the epileptic children was established by NONMEM method and auxiliary software,and the effects of fixed model such as demographic information,e GFR and drug combination on pharmacokinetics parameters were investigated.The final model was validated by the GOF plots,bootstrap method,and evaluated the accuracy of the model parameters by normalized prediction distribution errors?NPDE?.And establishing individualized drug delivery model by Monte Carlo.Result: The typical values of CL/F were 4.31 L·h-1 in the final model,V/F was fixed to 20 L.Body weight,daily dosage of Lev and glomerular filtration rate have a great influence on CL/F.The effect of 750 mg was the best in 30 kg children who took 500 mg of levetiracetam for 12 hours.Conclusion: This study preliminarily established PPK model of LEV in the epileptic children.It has been verified to be stable and reliable,which can predict LEV concentrations.And this model can offer reference for clinical medication. |
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