Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae

Abstract

Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (C_max) 0.56-7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC_0-24) 0.67-26.10 mg·h/L, and elimination half-life (T_1/2) 0.8-1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25-80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25-160 mg/kg, every 24 h) were conducted. The sigmoid E_max Hill equation was used to describe the dose-response data. The free-drug plasma fAUC_0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R² 0.9268). Median fAUC_0-24/MIC associated with static, 1-log₁₀ and 2-log₁₀ CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.

Keywords: breakpoint; nemonoxacin; neutropenic murine lung infection model; pharmacokinetics/pharmacodynamics; streptococcus pneumoniae.

FIGURE 1

Pharmacokinetics of nemonoxacin in plasma and epithelial lining fluid (ELF) following single subcutaneous doses at 2.5–80 mg/kg in neutropenic lung infected mice. Plasma was sampled at doses of 2.5, 10, 40 and 80 mg/kg. ELF was studied at doses of 2.5, 10 and 80 mg/kg. Groups of three mice were sampled for each time point. Each symbol represents the mean value of three mice. The error bar represents the standard deviations. Pharmacokinetic parameters including maximum drug concentrations (C_max), the AUC from 0 to 24 h (AUC_0-24), and elimination half-life (T_1/2) for each dose.

FIGURE 2

Correlation of pharmacokinetic/pharmacodynamic (PK/PD) indices fAUC_0-24/MIC (A), %fT > MIC (B) and fC_max/MIC (C) with efficacy for nemonoxacin in a neutropenic murine lung infection model caused by Streptococcus pneumoniae ATCC49619 in dose-fractionation study. Treatment was initiated at 2 h postinfection. Nemonoxacin was subcutaneously administered with a dosing range of 1.25–80 mg/kg, in once daily (q24h), twice daily (q12h), three times a day (q8h) and four times a day (q6h). Each circle represents data for each mouse. R ², the square of the correlation coefficient.

FIGURE 3

In vivo dose-response curves for nemonoxacin against six Streptococcus pneumoniae strains over a 24 h study period after a single dose administration in the neutropenic murine lung infection model. Each symbol represents the mean and standard deviation from three mice. The burden of organisms was measured at the start and end of therapy. The horizontal dashed line at 0 represents no net change from baseline.

FIGURE 4

Correlation between PK/PD index fAUC_0-24/MIC and efficacy of nemonoxacin against pooled data of six Streptococcus pneumoniae strains using a neutropenic murine lung infection model in dose-escalation experiment. Treatment was initiated at 2 h postinfection. Nemonoxacin was subcutaneously administered with single dose range of 1.25–160 mg/kg. Each point represents data for each mouse. R ², square of the correlation coefficient.

FIGURE 5

Probability of target attainment (PTA) of nemonoxacin in terms of fAUC_0-24/MIC ≥44.4 (2-log₁₀ CFU kill) following oral administration of nemonoxacin malate sodium chloride in healthy Chinese subjects, overlaid on the MIC distribution for S. pneumoniae.