Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers

Abstract

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

The plasma concentration (mean ± SD) versus time curves of nemonoxacin following multiple-dose intravenous infusions of 500 mg (at 5.56 mg/min over 1.5 h) or 750 mg (at 5.56 mg/min over 2.25 h) nemonoxacin malate once daily for 10 consecutive days in healthy subjects (n = 12 each). The symbols and lines indicate the observed values and predictions, respectively, by a two-compartment model.

FIG 2

The plasma concentration (mean ± SD) versus time curves of nemonoxacin following multiple-dose intravenous infusions of 500 mg (at 4.17 mg/min over 2 h), 650 mg (at 4.17 mg/min over 2.6 h), or 750 mg (at 4.17 mg/min over 3 h) nemonoxacin malate once daily for 10 consecutive days in healthy subjects (n = 12 in each cohort). The symbols and lines indicate the observed values and predictions, respectively, by a two-compartment model.

FIG 3

Probability of target attainment (PTA) of nemonoxacin in terms of fAUC0–24/MIC (target = 47.05) following intravenous infusion of nemonoxacin malate sodium chloride in healthy subjects. The horizontal dotted line indicates the PTA value of 90%. The infusion rate of nemonoxacin was 5.56 mg/min in stage 1 and 4.17 mg/min in stage 2.

FIG 4

Probability of target attainment (PTA) of nemonoxacin in terms of fCmax/MIC (target = 5.07) following intravenous infusion of nemonoxacin malate sodium chloride in healthy subjects. The horizontal dotted line indicates the PTA value of 90%. The infusion rate of nemonoxacin was 5.56 mg/min in stage 1 and 4.17 mg/min in stage 2.