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

Abstract

LCB01-0371, a new oxazolidinone with cyclic amidrazone under clinical development, has been shown to have a superior animal safety profile and better efficacy than those of linezolid. It works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. The aims of this study were to develop a population pharmacokinetics (PPK) model for oral LCB01-0371 in healthy Korean volunteers and to predict the plasma LCB01-0371 concentration over time on various dosing regimens of LCB01-0371 via Monte-Carlo simulation Pharmacokinetics (PK) data were collected from 110 healthy, Korean, male subjects in three Phase 1 studies for LCB01-0371. LCB01-0371 was administered at single or multiple oral doses of 50 ~ 3,200 mg, and blood and urine samples were collected serially for PK. Plasma and urine concentrations of LCB01-0371 were measured by validated LC/MS-MS. PPK analysis were performed using nonlinear mixed effect modeling software NONMEM (version 7.3) with the first-order conditional estimation with interaction (FOCE-I) method. Plasma LCB01-0371 was absorbed 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 exhibited that the final plasma and urine PPK model describe the data reasonably well. The current modeling and simulation analysis adequately characterized the pharmacokinetics of LCB01-0371 in Korean healthy adult male subjects, which will be a valuable tool in the search for the optimal dosing regimens of LCB01-0371.