Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections

Abstract

Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n = 77) or intravenously (n = 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]). Vc increased with body surface area, and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).

Keywords: clinical trials; finafloxacin; pharmacodynamics; population pharmacokinetics; urinary tract infection.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Plots of individual predicted versus measured plasma concentrations stratified by trial. Plots of individual predicted versus measured plasma concentrations of finafloxacin in healthy volunteers receiving intravenous administrations (a), patients receiving intravenous administrations (b), and healthy volunteers receiving oral administrations (c), as obtained from the final model. Solid line, unity line; dashed line, line of best fit.

FIG 2

Empirical Bayes estimates of elimination clearances stratified by the dose level of finafloxacin. Empirical Bayes estimates of elimination clearances are stratified by the dose (200 to 1,000 mg/day) from healthy volunteers receiving intravenous infusions of finafloxacin. Dots, medians; bars, 90% intervals. A trend toward diminished clearances can be seen at the highest dose of 1,000 mg.

FIG 3

Goodness-of-fit plots of the final model incorporating the whole data set. Shown are goodness-of-fit plots of the final model incorporating plasma data from healthy volunteers receiving oral or intravenous administrations and from patients receiving intravenous administrations. The top row shows individual and population predicted versus measured plasma concentrations; the bottom row shows population predicted concentrations and the time after dose versus conditional weighted residuals. Solid lines indicate the unity line (top) or the line of zero residuals (bottom); dashed lines indicate lines of best fit.