Safety, tolerability and pharmacokinetics of 21 day multiple oral administration of a new oxazolidinone antibiotic, LCB01-0371, in healthy male subjects

Abstract

Background: LCB01-0371 is a new oxazolidinone antibiotic, which targets most Gram-positive organisms. High rates of adverse reactions including myelosuppression have been reported for existing oxazolidinones, limiting their long-term use. Objectives: The safety, tolerability and pharmacokinetics (PK) of 21 day multiple oral administrations of LCB01- 0371 in healthy male subjects (clinicaltrials.gov: NCT02540460) were investigated. Methods: In this randomized, double-blind, placebo-controlled study, subjects received 800mg of LCB01-0371 once or twice daily or 1200mg of LCB01-0371 twice-daily for 21 days in a fasting state. Safety and tolerability profiles including laboratory tests were evaluated during the study and on a post-study visit and the results were analysed using repeated-measures analysis of variance (RM-ANOVA). Serial blood samples for PK analysis were collected up to 12 h after dosing on day 21. Results: A total of 40 subjects were enrolled and 34 subjects completed the study. Two subjects dropped out according to stopping rules. In the 1200mg twice-daily dose group, the absolute value of red blood cell count, haematocrit and haemoglobin decreased by 500%106/L (6.5%), 4.5% (6.8%) and 1.6 g/dL (6.9%), respectively, after 21 day administrations of LCB01-0371. However, mean relative changes from baseline of all haematology values were not significantly different among doses, including placebo (all, P,0.05). PK profiles of LCB01-0371 in the dose range of 800mg once daily to 1200mg twice daily were consistent with previous studies. Conclusions: LCB01-0371 is well tolerated in healthy male subjects with comparable haematology profiles to placebo, after multiple doses of up to 1200mg twice daily for 21 days.