Pharmacokinetics, pharmacodynamics, and tolerability of single-dose oral LCB01-0371, a novel oxazolidinone with broad-spectrum activity, in healthy volunteers [PublishAheadOfPrint]

LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses (NCT01554995). Single oral doses of 600 mg Linezolid, a placebo, or LCB01-0371 between 50 mg and 3200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, and LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and Linezolid were determined. LCB01-0371 was well tolerated up to 2400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil count, and increased total bilirubin. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose-proportional over the range of 50mg--800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for S. pneumonia, and the potency of LCB01-0371 at 800 mg was similar to that of Linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than Linezolid. Taken together, LCB01-0371 was well tolerated and exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of Linezolid. These results support the further clinical development of LCB01-0371.

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