| Teicoplanin is commonly used to treat infections caused by Gram-positive bacteria,especially those caused by methicillin-resistant Staphylococcus aureus.The instructions for teicoplanin for injection clearly indicate that the protein binding rate of teicoplanin is about 90%,so the clinically commonly used method of doubling the first dose and maintaining the dose quickly reaches the therapeutic blood concentration.Because teicoplanin is almost entirely excreted by the kidneys,the pharmacokinetics of teicoplanin in patients with renal insufficiency are highly variable.Objective:?1?A simple high-performance liquid chromatographic method was developed for determining the concentration of teicoplanin in human plasma,and the five major components of teicoplanin was designated as A2-1,A2-2,A2-3,A2-4 and A2-5.This provides a methodological basis for clinical monitoring of teicoplanin plasma concentration and adjustment of dosing regimen.?2?Establish a population pharmacokinetic model of teicoplanin in patients with renal insufficiency,and quantitatively investigate the factors affecting biochemical indexes of pharmacokinetics and combined medication of teicoplanin,and verify the stability,reliability and predictability of the teicoplanin pharmacokinetic model through internal verification,with a view to providing theoretical support for the formulation of individualized drug delivery plans for teicoplanin.Methods:?1?A high performance liquid chromatography method was developed for the determination of teicoplanin concentration in human plasma?A2-1,A2-2,A2-3,A2-4and A2-5?,chromatographic conditions for the determination by HPLC are as follows:Selection Column Cosmosil C18?4.6 mm×250 mm,5?m?,the five main components of teicoplanin in human plasma were detected at the mobile phase of acetonitrile:0.05mol·L-1 KH2PO4=27:73,detection wavelength:245 nm,a flow rate of 1.0 m L·min-1,a column temperature of 30?and a sample volume of 10?L.Using the internal standard for quantification,and sulfamethoxazole was selected as the internal standard,which was applied to the clinic after methodological investigation.?2?The clinical data of 50 patients with renal insufficiency treated with teicoplanin intravenous drip in the Department of The First Affiliated Hospital of Anhui Medical University were collected.The use of established human plasma concentrations of teicoplanin methodology to measure plasma concentrations of teicoplanin patients collected.Collected 202 blood concentration monitoring data of 50 patients.The non-linear mixed effects model?NONMEM?method was used to establish the population pharmacokinetic model of teicoplanin in patients with renal insufficiency by examining the effects of fixed and random effect factors such as gender,age,weight,serum total protein,albumin,C-reactive protein,liver and kidney function indicators,and combined medication on the pharmacokinetic parameters of teicoplanin.Using goodness of fit diagnostic plot for assessing the advantages and disadvantages of model curve fitting,and using bootstrap to investigate the reliability and stability of the final model,and the normal prediction distribution error?NPDE?is used to evaluate the prediction performance of the final model.Results:?1?The five main component peaks of teicoplanin are well separated from the internal standard peak and its endogenous substance peak.The human plasma concentration of teicoplanin is 2?100?g m L-1,and its peak area ratio to the peak area of teicoplanin piperacillin and sulbactam follows linear function y=0.1112x-0.124,r=0.998?n=7?,the lower limit of quantitation of 2?g m L-1,the extraction recovery is 86.26?94.15%,and the method recovery is 85.70?104.06%.And that method was used for the detection of teicoplanin concentration in plasma samples of patients with clinical renal insufficiency.?2?The average age of 50 patients with renal insufficiency of intravenous teicoplanin is a population pharmacokinetic model of teicoplanin in patients with renal insufficiency was established based on 202 plasma concentrations and related clinical data of 50 cases of teicoplanin in patients with renal insufficiency.In line with the one-bedroom model,the final model formula is:CL?CL/F??L/hr?=0.329*?TP?g/L?/57.7?2.09;V?L?=48.4The typical population values of the apparent clearance?CL/F?and apparent volume?V/F?of the final model were 0.329L/h and 48.4L,respectively.Serum total protein concentration is an important determinant of teicoplanin PK variability.Patients with renal insufficiency should consider serum total protein concentration when determining the dosing regimen.Through internal verification,GOF,NPDE,and Bootstrap results all show that the model prediction results are reliable.Conclusion:?1?This study successfully established a high-performance liquid chromatography method to determine the concentration of teicoplanin in human plasma.?2?This study successfully established a population pharmacokinetic model of teicoplanin in patients with renal insufficiency.Through internal verification and normalized prediction distribution errors,it shows that the model is stable and effective,and the prediction performance is good.With a view to improving the clinical treatment of drugs and reduce the incidence of adverse reactions. |
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