Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

Abstract

Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).

Keywords: antimicrobial agents; clinical trials; finafloxacin; pharmacology.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Geometric mean plasma concentrations of finafloxacin following single and multiple intravenous doses. Geometric mean and standard deviation finafloxacin plasma concentrations on the last day of treatment following single (part A, left) or multiple (part B, right) 1-h intravenous infusions are shown on a semilogarithmic scale for all dose levels. Time is relative to the start of infusion. The dashed lines indicate the limit of quantification.

FIG 2

Relationship between dose and pharmacokinetic parameters of finafloxacin following single and multiple intravenous doses. Geometric means and standard deviations of AUCinf (top left; day 1 for single and multiple doses), AUC0–tlast (bottom left; 0 to 24 h postdosing on day 1 for single doses and 0 to 72 h postdosing on day 7 for multiple doses), Cmax (top right; day 1 for single doses and day 7 for multiple doses), and t1/2 (bottom right; day 1 for single doses and day 7 for multiple doses) following single (▲) and multiple (•) 1 h intravenous infusions of 200 to 1,000 mg finafloxacin. A deviation from dose linearity is apparent at higher doses. Bars indicating standard deviations point upwards for multiple administrations and downwards for single administrations.

FIG 3

Cumulative urinary excretion of finafloxacin following a single intravenous dose. Geometric means and standard deviations of the cumulative fractions of finafloxacin doses excreted in urine (fe) on the last day of treatment following single (part A; left) and multiple (part B; right) 1-h intravenous administrations are shown. Time is relative to the start of the infusion.