New Oxazolidinone MRX-I PK-PD Study

MRX-I is a novel oxazolidinone antibiotic agent currently being developed by MicuRx.Informations regarding its in vivo pharmacokinetics and pharmacodynamics in preclinical animal models provide valuble rational and justification for its clinical development.In this study,MRX-I pharmacodynamics was evaluated in mouse models of immunocompromised mice with thigh infections due to Staphylococcus aureus and Streptococcus pneumoniae and the potency was correlated with pharmacokinetics.The most relavant PK/PD parameter was predicted using nonlinear regression analysis and the static doses were calculated using a sigmoidal dose-response model.Following a single oral dose of 20 and 80 mg/kg in neutropenic mice with S.aureus infection(MIC=1-2 μg/ml against S.aureus),MRX-I Cmax was 16.2 and 46.0 μg/ml and AUC24h 30.8 and 121.0 μg*h/ml,respectively.MRX-I efficacy against S.aureus and S.pneumoiae was evaluated as logCFU reduction per thigh comparing to control and MRX-I was effective in treating infections due to S.aureus and S.pneumoiae of wild type and resistant clinical isolates.In dose fractionation studies,the 24h(AUC)/MIC was determined to be the best correlated PKPD parameter predicting MRX-I efficacy against S.aureus with R2=91.1%for AUC/MIC,versus R2=62.9%for%T>MIC and R2=86.0%for the Cmax/MIC.The static doses against eight strains of S.aureus(four MRSA and four MSSA)ranged from 22.0 to 140.0 mg/kg/24h with a mean of 77.0±39.7 mg/kg/24h.The static doses against four S.pneumoiae strains ranged from 21.0 to 62.0 mg/kg/24 h(one PSSP,one PISP and two PRSP)with a mean of 33.3 ± 19.3 mg/kg/24 h.Following a single oral dose of 10 and 40 mg/kg in normal mice with S.aureus infection(MIC=1-2 μg/ml against S.aureus),MRX-I Cmax was 9.4 and 30.1μg/ml and AUC24h 19.6 and 85.4 μg*h/ml,respectively.MRX-I efficacy against S.aureus was evaluated as logCFU reduction per thigh comparing to control and MRX-I was effective in treating infections due to S.aureus of wild type and resistant clinical isolates.The static doses against two strains of S.aureus(1 MSS A and 1 MRS A)ranged from 8.8 to 12.7 mg/kg/24h with a mean of 10.7 ±2.8 mg/kg/24h.In all,The 24-h area under the concentration time curve AUC/MIC ratio was the major parameter determining the efficacy of linezolid against S.aureus.MRX-Ishowed good in vivo efficacy against the local infection of MRSA and PRSP clinical strains.In normal mice thigh infection model,the AUC24hMIC ratio required for a bacterial static effect with MRX-I was 19.9.According to the protein binding of MRX-I,AUC 24h/MIC of human achieved 107 to target the efficacy.Based upon a pharmacokinetic goal of a 24h AUC/MIC of 107,a dosage regimen of 965 mg given orally daily would achieve success against organisms with MICs as high as 0.5 to 2 μg/ml.