Pharmacokinetic Modeling and Simulation Analysis of LCB01-0371, a New Oxazolidinone Antibiotic Under Clinical Development

Aims: LCB01-0371 is a new oxazolidinone antibiotic with cyclic amidrazone under clinical development. It exerts its anti-bacterial activity by binding to bacterial ribosomes, thereby inhibiting protein synthesis of the bacteria. The purpose of this study was to explore the pharmacokinetics (PK) of oral LCB01-0371 in healthy Korean volunteers, to predict the plasma LCB01-0371 concentration over time on various dosing regimens of LCB01-0371 via Monte-Carlo simulation.

Methods: PK data from 110 healthy, Korean, male subjects in three phase 1 studies for LCB01-0371 were used for this analysis. The subjects received single or multiple oral doses of LCB01-0371 in 50 ~ 3,200 mg, and blood and urine were collected serially for PK. Plasma and urine concentrations of LCB01-0371 were measured using validated LC/MS-MS. PK were analyzed by nonlinear mixed effect modeling implemented in NONMEM (version 7.3).

Results: Plasma LCB01-0371 was absorbed very fast after oral administration with followed by rapid decline in plasma concentration. The LCB01-0371 concentration in plasma and amount excreted in urine over time were best described by two-compartment model (central Vd, 82.4 L; peripheral Vd, 8.59 L) with absorption lag (ALAG1, 0.212 hour) and mixed zero (D1, 0.286 hour) and first order absorption (Ka, 80.7 /hour) process. Basic goodness of fit plots, visual predictive check plots showed that the final plasma and urine PK model describe the data reasonably well.

Conclusion: The current modeling and simulation analysis characterized the pharmacokinetics of LCB01-0371 in Korean healthy normal male subjects, which will be useful in identifying the optimal dosing regimens of LCB01-0371.