Single-dose Intravenous Safety, Tolerability, and Pharmacokinetics and Absolute Bioavailability of LCB01-0371

Abstract Purpose LCB01-0371 is a novel broad-spectrum oxazolidinone antibacterial agent under investigation for the treatment of infection by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus . This study evaluated the safety, tolerability, and pharmacokinetics of LCB01-0371 after a single intravenous (IV) infusion and determined its absolute oral bioavailability at a therapeutic dose of 800 mg. Methods : This study was conducted in 2 parts. The first part was a single-blind, placebo-controlled, escalating single IV dose study (200, 400, 800, and 1200 mg) of LCB01-0371 via 2 different infusion regimens (250 mL over 60 min or 150 mL over 30 min) in 36 healthy male volunteers. The second part was an open-label, 2-way crossover design study in which 8 subjects were randomly assigned to 1 of 2 sequences of a single oral (800 mg) or IV (400 mg) administration of LCB01-0371. Safety assessments were conducted at regular intervals. Blood and urine were serially sampled, and drug concentrations were measured for up to 24 h to calculate pharmacokinetic parameters. Findings LCB01-0371 after IV administration was generally safe and well tolerated up to 800 mg regardless of the infusion regimen. Adverse events were mild, excluding nausea at the highest dose, and resolved spontaneously. After a single IV administration, LCB01-0371 exhibited linear pharmacokinetic properties over the range of 200–800 mg. The elimination t 1/2 , volume of distribution, and clearance ranged from 1.48 to 1.68 h, 57.74–76.72 L, and 33.17–43.31 L/h, respectively, and they remained unchanged over the corresponding dose range. C max , AUC 0–last , and AUC 0–∞ increased in a dose-dependent manner. The dose-normalized total exposure after single PO and IV dosing were equivalent, with 90% CIs of the geometric least squares mean ratio of 86.6%–110% for AUC 0–last and 86.6%–111% for AUC 0–∞ . The dose-normalized C max was not equivalent between oral and IV dosing, with a 90% CI of the geometric least squares mean ratio of 50.0%–105%. The absolute oral bioavailability of LCB01-0371 after a single 800-mg dose was 99.75%. Implications After a single IV administration, LCB01-0371 was well tolerated in healthy volunteers at doses up to 800 mg, and it exhibited linear pharmacokinetic properties. The comparable total systemic exposure between IV and oral administration supports the ability to switch administration routes without a need for dose adjustment. ClinicalTrials.gov identifier: NCT02882789 .