Safety and pharmacokinetics of MRX-I at therapeutic and supratherapeutic doses in healthy Chinese subjects and assessment of MRX-I dosing regimens based on pharmacokinetic-pharmacodynamic analysis

【摘要】：Objectives:To assess the safety and pharmacokinetics of a new-generation oxazolidinone MRX-I and a major inactive metabolite M2 after single oral administration of 800,1200 and 1600 mg under the fed condition;and to evaluate three dosing regimens against methicillin-resistant Staphylococcus aureus(MRSA) infections based on pharmacokinetic/pharmacodynamic(PK/PD) analysis.Methods:Twenty healthy subjects received a single oral dose of 1200 or 1600 mg of MRX-I or placebo under fed condition in a double blind,placebo-controlled dose escalation tolerance study.Fifty-two subjects received single doses of 800 mg of MRX-I under fed condition in a blinded,randomized,single-center,four-periods,4-crossover thorough QT study.Noncompartmental analysis were used to evaluate the pharmacokinetics of MRX-I and M2.Steady-state concentrations of MRX-I following different dosing regimens(800,1200,and 1600 mg every 12 h) were simulated employed a newly developed two-compartment PK model.The minimum inhibitory concentration distribution of MRX-I was analyzed in 348 Staphylococci clinical isolates.Monte Carlo simulations were conducted to attain probability of target attainment(PTA),and cumulative fraction of response(CFR) to predict the efficacy of the three regimens.Results:All three doses ranging from 800 to 1600 mg of MRX-I were well tolerated in the healthy subjects under fed condition,and nonlinear PK was observed after single oral administration(Table 1,Table 2,Table 3 and Figure 1).The mean plasma exposure of M2 to that of MRX-I exceeded 10% in the three groups.Both MIC_(50) and MIC_(90)(MICs to inhibit the growth of 50 and 90% of microorganisms,respectively) of MRX-I against MRSA were 0.5 mg/L(Table 4).PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12 h was efficacious against infections caused by MRSA with an MIC≤1 mg/L(PTA90% and CFR90%)(Figure 2).Conclusions:MRX-I is a safe option against MRSA even at a suprathepeutic dose of 1600 mg.The regimen of 800 mg q 12 h could achieve great efficacy for the bacterial infections caused by MRSA.The is the first PK/PD study to predict 800 mg q 12 h is sufficient to treat MRSA infections with an MIC≤1 mg/L.A Phase Ⅲ study with this suggested dosing regimen is being conducted.