Design The Best Dosing Regimen Of Norvancomycin

Objective: Study the human pharmacokinetic (PK) and pharmacodynamics (PD)in vitro of norvancomycin. Then the PK/PD computer model of norvancomycin wasset up by Monte Carlo simulation application of crystal ball software based on thepharmacokinetic and pharmacodynamic data of norvancomycin. Get the cumulativefraction of response of norvancomycin against different bacteria under differentdoseage. Then according to the size of CFR, promote the clinical rational practice ofnorvancomycin.Method: First of all, the HPLC determination method of norvancomycin wasestablished. Then study the human pharmacokinetic of vancomycin based on theestablished HPLC determination method. In selected volunteers, single dosenorvancomycin was administration through intravenous drip with400mg,800mgand1600mg. Using DAS3.0software, according to the measured blood drugconcentration-time data, calculated to norvancomycin main pharmacokineticparameters; Then apply trace double dilution method and constant double dilutionmethod, determined the MIC distribution of norvancomycin against staphylococcusaureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), Enterococcusfaecium and Enterococcus faecalis, epidermis staphylococcus (SE) andmethicillin-resistant staphylococcus (MRSE); Finally application of crystal ballsoftware, set400as the target value of AUC0~24/MIC, make1000times,5000times and1000times of Monte Carlo simulation based on the experiment ofpharmacokinetic parameters and (MIC) distribution in vitro. Get the PTA under aparticular MIC and cumulative reaction fraction (CFR).With the size of the PTA orCFR90%or greater as the best dosage regimen. Results: The main pharmacokinetic parameters of400mg,800mg,1600mg dosegroups: half-life T1/2is3.99±0.85h、4.15±0.73h and3.82±0.86h respectively;Peak concentrations, Cmax respectively was28.84±4.08μg/ml、56.95±6.86μg/mland123.78±18.74μg/ml; The area under the plasma drug concentration-timecurve AUC0-24was64.43±11.50μg.h/ml、126.3±19.53μg.h/ml and276.08±33.09μg.h/ml respectively；AUC0-∞was66.04±10.88μg.h/ml、128.32±19.22μg.h/mland284.50±34.79μg.h/ml respectively.Main pharmacodynamics parameters: norvancomycin for MSSA: MIC50, MIC90andMICrange is0.25μg/ml,0.5μg/ml and0.25to1.0μg/ml respectively; For MRSA:MIC50, MIC90and MICrange is0.5μg/ml,1.0μg/ml and0.25to1.0μg/mlrespectively; for enterococcus faecium: MIC50and MIC90and MICrange is0.25μg/ml,0.5μg/ml and0.25to1.0μg/ml respectively; for Enterococcus faecalis:MIC50, MIC90and MICrange is0.25μg/ml,0.5μg/ml and0.25to1.0μg/mlrespectively;for SE MIC50, MIC90and MICrange is2.0μg/ml,2.0μg/ml and1.0to4.0μg/ml respectively; For MRSE MIC50, MIC90and MICrange is2.0μg/ml,4.0μg/ml and1.08.0μg/ml respectively.The PK/PD results of norvancomycin simulated by Monte Carlo simulation: toMSSA, the average CFR value of400mg,800mg,1600mg dose group after1000times,5000times and the of10000times simulation is24.02%,71.90%and24.02%respectively.To MRSA, the average CFR value of400mg,800mg,1600mg dosegroup after1000times,5000times and the of10000times simulation is3.97%,22.37%and3.97%respectively; To enterococcus faecium, the average CFR value of400mg,800mg,1600mg dose group after1000times,5000times and the of10000times simulation is14.74%,44.95%and14.74%respectively; To Enterococcusfaecalis, the average CFR value of400mg,800mg,1600mg dose group after1000times,5000times and the of10000times simulation is11.36%,41.78%and11.36% respectively.For SE and MRSE, when set AUC/MIC value as400or higher, in the400mg and800mg dose group, the CFR value was close to0. Only at1600mg dose group, theaverage CFR value were6.08%and2.09%respectively, the RSD%value of threesimulation were7.44and21.77respectively.Conclusion：There had a better clinical effect for norvancomycin against MSSA,Enterococcus faecium and Enterococcus faecalis infections at1600mg dosageregimen. Norvancomycin can be separately used in the treatment of the infectioncaused by these strains. For the infection caused by MRSA, SE and MRSE, even at1600mg dose regimen, the CFR%value was only64.04%,6.08%and2.19%respectively. For SE and MRSE, there may have their own special target value(AUC/MIC value, AUMC), and this value may be80. For MRSA, althoughcompared with other drugs, the clinical effect is good, but a single application can bedifficult to achieve good clinical effect, even may be result in treatment failure. ANDit can be used combined with other drugs.