Optimization Of The Clinical Dosage Regimen For Moxifloxacin Based On Monte Carlo Simulation

Objective:Combined with moxifloxacin’s adverse drug reaction,to optimize the clinical dosage regimen of moxifloxacin through the application of Monte Carlo simulation.Methods:1.This study collected,from 2000 to 2017,77 cases of ADR of moxilfoxacin from medical literature reports.By using the computer aided tools,on the content of articles for screening,recording and analysis,then finally carried on the summary analysis and suggestion on rational drug use.2.This study applied standard trace both double dilution method to determine the MIC distribution of moxifloxacin against 1011 strains of clinical isolates in vitro.And established a neutropenic-mouse thigh infection model to evaluate the antibacterial effects in vivo,respectively.3.Based on PK/PD theory,calculation of CRF and PTA values after three dosage treatments(ie,400 mg qd,800 mg qd and 1200 mg qd)were modelled by using Monte Carlo simulation,which was repeated 10000 times.Estimate value of AUC0-24/MlC ≥125 was expected to be the pharmacodynamic target of obtaining satisfactory clinical therapeutic effect for inpatients,and AUC0-24/MlC ≥30 was expected to be the pharmacodynamic target for outpatients.According to the different AUC0-24/MlC ratios and respective probability distribution,the dosage of CFR≥90% as the optimal dosage regimen.Results:1.Moxifloxacin is influential to many kinds of organization and internal organs of human body,including blood and lymphatic reactions,digestive system reactions,nervous system reactions,allergins reactions,respiratory reactions,etc.In the 77 cases of ADR,male patients account for 58.44%,female account for 41.56%,the male to female ratio is 1.41:1.The cases of ADR are the most in senile group aged over 50,there are 56 cases,account for 72.72%.It is the most of ADR occurred in intravenous drip(50.65%),followed by oral administration(35.06%).In addition,there are some cases of compatibility of drugs,accounted for 61.04%.2.The sensitive rate of moxifloxacin against 1011 strains of clinical isolates is 9.7%~100%.And the main pharmacodynamics parameters are: for MSSA,MIC50,MIC90 and MICrange is 0.12,1 and ≤0.03-2μg/ml respectively.For MRSA,MIC50,MIC90 and MICrange is 2,2 and 0.06-4μg/ml respectively.For PSSP,MIC50,MIC90 and MICrange is 0.06,0.25 and ≤0.03-4μg/ml respectively.For PISP,MIC50,MIC90 and MICrange is 0.12,0.5 and ≤0.03-8μg/ml respectively.For H.inf,MIC50,MIC90 and MICrange is ≤0.03,0.12 and ≤0.03-1μg/ml respectively.For KPN,MIC50,MIC90 and MICrange is 0.5,2 and ≤0.03-8μg/ml respectively.For M.cata,MIC50,MIC90 and MICrange is ≤0.03,0.12 and ≤0.03-0.12μg/ml respectively.For E.coli,MIC50,MIC90 and MICrange is 0.12,0.5 and ≤0.03-8μg/ml respectively.For ENT,MIC50,MIC90 and MICrange is 0.12,0.25 and ≤0.03-2μg/ml respectively.In addition,After the treatment with moxifloxacin for 24 h,the bacteria in mouse thigh muscle is almost completely killed except for MRSA and E.coli,which is consistent with results in vitro.3.Using 10000 patients Monte Carlo simulation,the CRF and PTA results of moxifloxacin are: for AUC0-24/MlC ≥125,CRF value is above 90% to H.inf and M.cata when dosage regimen is 400 mg qd.CRF value is above 90% to H.inf,M.cata and ENT when dosage regimen is 800 mg qd.And CRF value is under 90% to MSSA,MRSA and KPN when dosage regimen is 1200 mg qd.The PTA against all bacteria with 0.12 is above 90% for mocifloxacin 400 mg qd,800 mg qd and 1200 mg qd,respectively.For AUC0-24/MlC ≥30,CRF value is under 90% to MSSA,MRSA and KPN when dosage regimen is 400 mg qd.CRF value is under 90% to MRSA when dosage regimen is 800 mg qd.And CRF value is above 90% to all bacteria when dosage regimen is 1200 mg qd.The PTA against all bacteria with 0.5μg/ml are above 90% for mocifloxacin 400 mg qd,800 mg qd and 1200 mg qd,respectively.Conclusion:Based on safety,it is recommended that increase moxifloxacin dose can reach satisfactory clinical effect.For inpatients,the alternative dosage regimens of moxifloxacin for infectious H.inf and M.cata is 400 mg qd,for infectious ENT is 800 mg qd,and for infectious PSSP,PISP and E.coli is 1200 mg qd.However,to achieve satisfactory clinical curative effect and effectively prevent the drug resistance,for infection caused by MSSA,MRSA and KPN given combination therapy is an optimal dosage regimen.For outpatients,the alternative dosage regimens of moxifloxacin for infectious PSSP,PISP,H.inf,M.cata,E.coli and ENT is 400 mg qd,for infectious MSSA and KPN is 800 mg,and for infectious MRSA is 1200 mg qd or drug combination.In addition,clinical physicians should pay more attention to ADR of moxifloxacin to improve the rational use.