Pharmacokinetic and pharmacodynamic evaluation of the lantibiotic MU1140

Presented are the pharmacokinetics (PK), exposure-response relationship, and the PK/pharmacodynamic (PD) index predictive of maximum therapeutic efficacy for the lantibiotic MU1140. MU1140, at a dose of 12.5 or 25 mg/kg, was administered intravenously, to characterize its PK parameters in rat. The recently developed in vitro PD model of MU1140 activity was enhanced by incorporation of the PK of MU1140 in rat. The linked PK/PD model was used in a simulation study to determine the PK/PD index predictive of in vivo efficacy. MU1140 total plasma concentration-time profiles declined biexponentially with elimination terminal half-life of 1.6 +/- 0.1 h. Rapid injection of MU1140 was associated with a hypersensitivity reaction that can be blocked by premedication with diphenhydramine. The simulation study revealed that Staphylococcus aureus concentrations correlated with T > MIC making it the PK/PD index best predictive of efficacy. Collectively, these findings suggest that the best route of administration of MU1140 is slow infusion which will increase the time its concentration remains above the MIC, thus maximizing the therapeutic effect and minimizing the observed toxicity.