Multiple-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral LCB01-0371 in Healthy Male Volunteers.

Purpose: LCB01-0371 is a novel oxazolidinone broad-spectrum antibacterial that is more potent than linezolid against systemic infections in animals. The goal of this investigation was to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple-dose LCB01-0371 as well as the pharmacokinetic characteristics of a new 400-mg tablet formulation.

Methods: Thirty-two healthy male subjects received BID 400-1600 mg multiple oral dosing of LCB01-0371 (200-mg tablet or 400-mg tablet) for 7 days, and 6 subjects received an 800-mg single oral dose of LCB01-0371 (400-mg tablet). Safety assessments were undertaken at regular intervals. Blood and urine were sampled, and drug concentration and inhibitory and bactericidal titers were measured.

Findings: LCB01-0371 was generally safe and well tolerated up to 1200 mg BID for 7 days. Adverse events were mild, except for headache, nausea, and dizziness at the dose of 1600 mg, and resolved spontaneously. LCB01-0371 was absorbed rapidly within 2 h after administration, and its accumulation observed on day 7 ranged between 1.10- and 1.46-fold. The elimination t1/2 was 1.64-1.94 h, which remained unchanged across all doses. AUC and C were not dose proportional across the dose range from 400 to 1200 mg after both single and multiple dosing, indicating a nonlinear pharmacokinetic profile. The percentage of the dose excreted via the urine ranged from 7.84% to 8.95%. The new (400-mg tablet) formulation exhibited less interindividual variability with pharmacokinetic characteristics similar to the original formulation (200-mg tablet). LCB01-0371 exhibited both early serum inhibitory and bactericidal activities against the 4 strains tested in the ex vivo pharmacodynamics study.

Implications: BID doses of LCB01-0371 up to 1200 mg for 7 days were well tolerated and exhibited rapid serum inhibitory and bactericidal activities against common gram-positive pathogens. The results warrant further clinical investigation of the antibacterial effect of BID LCB01-0371 administration. ClinicalTrial.gov identifier: NCT01842516.