Population Pharmacokinetics Study of Nemonoxacin Among Chinese Patients With Moderate Hepatic Impairment

Purpose

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment.

Methods

An open-label, single-dose, parallel group (moderate hepatic impairment group and healthy control group) PK study of nemonoxacin was conducted. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was performed to detect the unchanged nemonoxacin concentration in blood and urine samples. The nonlinear mixed effects modeling tool NONMEN (version 7.3) was used to conduct the population PK analysis. The paired-t test was conducted to compare the PK parameters of the hepatic impairment group and the healthy control group by SPSS (Version 17.0).

Findings

Ten subjects for each group were enrolled into the PK study. The PK parameters as well as the plasma concentration-time and logarithmic concentration-time profiles after taking a 500-mg single dose of nemonoxacin showed few differences between the two groups (P > 0.05). The mean areas under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72 h) of the moderate hepatic impairment group and the healthy control group in the nemonoxacin PK study were 58.50 (17.30) mg·h/mL and 49.74 (10.16) mg·h/mL, respectively, giving a mean (SD) AUC0-72 h ratio of 1.15 (0.42) with a 90% CI of 0.91–1.39. A 3- compartment model was considered to be the best model for the data, especially in fitting the plasma point at low drug concentrations. Covariate analysis indicated that weight affected CL/F, V1/F, and V3/F and that eGFR only affected CL/F in the power function model, while gender affected V3/F in the linear model by forward selection and backward deletion.

Implications

The population PK parameters of nemonoxacin were evaluated in patients with hepatic impairment. The hepatic function did not have a significant impact on the PK parameters of nemonxacin, but renal function was a meaningful covariate that is consistent with its PK characteristics. In this study, nemonoxacin was well tolerated in the patients with moderate hepatic impairment as well as in the healthy subjects. Based on these data, it is not necessary to consider dose adjustment of nemonoxacin in patients with mild or moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02604498.