Population Pharmacokinetics Study Of Teicoplanin In Adult Patients

Objective1.To establish a high performance liquid chromatographic method for determination of teicoplanin in human plasma and using it for clinical therapeutic drug monitoring.2.To establish a population pharmacokinetic(PPK)model to investigate the distribution characteristics of the pharmacokinetic parameters of teicoplanin in Chinese adult patients,and provide reference for clinical personalized medication.Method1.The high performance liquid chromatographic separation was carried out by reversed phase chromatography on a Agilent symmetry C18 column(4.6×250 mm id,5?m particle size)with a phase composed of NaH2PO4(0.01mol·L-1):acetonitrile(74:26,v/v,pH was adjusted to 3.10 with phosphoric acid),pumped isocratically at a flow rate of 1.0 mL min-1,The injection volume was 20 ?L,The effluent was monitored at 215 nm.And the temperature of column was about 35 ?.2.Prospectively collected patients who received teicoplanin from October 2017 to January 2019.High performance liquid chromatographic was used to determine plasma concentration of teicoplanin.Collecting their clinical data,and evaluating their clinical efficacy,then analysing the relationship)between the concentration and clinical efficacy.Nonlinear mixed effect modeling(NONMEM)was employed to establish the PPK model.The effects of gender,age,body weight,serum albumin,glomerular filtration rate and other medication on the pharmacokinetic parameters of teicoplanin were investigated.The performance of-final model was internally assessed by goodness of fit and bootstrap,normalized prediction distribution error(NPDE)and external verification to evaluate the stability and predictive abilityResult1.The standard curves for teicoplanin were constructed by concentration versus the ratio of TA2-2 to piperacillin sodium of peak area and showed good linearity in a concentration range from 3.125 to 100 mg·L-1 of teicoplanin.The correlation coefficient was 0.9998.And the limit of detection was 2.0 mg·L-1.The low limit quantitation was 3.125 mg·L-1.The accuracy of intra and inter-day were both greater than 95%.The relative standard deviation(RSD)of intra and inter-day were both less than 10%.And the extraction recovery was greater than 80%.2.Among 123 patients,70 patients were monitored for plasma concentration after 72 hours of administration.And the efficacy evaluation was completed.The effective rate was 82.9%(58/70).Spearman correlation analysis showed that the plasma concentration was related to the efficacy(P<0.05),The coefficient was 0.57.The plasma concentration of 36 patients with the same dose regimen ranged from 3.5 to 31.3 mg·L-1,the differences of concentration among different patients were significant.3.The established population pharmacokinetics model of teicoplanin fit one-compartment model of first-order absorption and elimination,The clearance was significantly associated with glomerular filtration rate(GFR),body weight(BW)and serum albumin.Gender,age and combined drug didn't alter the teicoplanin clearance.The final fitted population pharmacokinetic model of teicoplanin was:CL{L/h)=1.22 ×(GFR/80)0 757 ×(BW/60)1.05 ×(31/Alb)1.04 ×e0.274 V(L)=70.1The stability and the predictive performance were accepted by goodness of fit,bootstrap,normalized prediction distribution error and external verification.Conclusion1.A sensitive,accurate and simple high performance liquid chromatographic for quantification of teicoplanin was developed and fully validated.All parameters meet the acceptance criteria for method validation according to the Chinese Pharmacopoeia and the method shoes range,linearity,precision,accuracy and recovery.The results showed the proposed method is suitable for therapeutic drug monitoring of teicoplanin.2.Plasma concentration of teicoplanin is related to the efficacy.The differences of teicoplanin concentration among different patients were significant.3.The population pharmacokinetic model of teicoplanin in Chinese adult patients has been established for the first time in this study.And the population phamacokinetic model may provide a scientific basis to optimized medication.