title: Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers.
abstract: OBJECTIVE
  The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined.
  
  
  METHODS
  Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated.
  
  
  RESULTS
  Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC0-∞ and 0.8445 (0.8090-0.8815) for AUC0-t, respectively. The Cmax values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150-0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%.
  
  
  CONCLUSIONS
  Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.
authors.affiliation: Melinta Therapeutics, Lincolnshire, Illinois.
authors.forename: Randall
authors.initials: R
authors.lastname: Hoover
authors.affiliation: PPD, Austin, Texas.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunt
authors.affiliation: PPD, Austin, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Benedict
authors.affiliation: Pharma Start LLC, Northbrook, Illinois.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Paulson
authors.affiliation: Melinta Therapeutics, Lincolnshire, Illinois.
authors.forename: Laura
authors.initials: L
authors.lastname: Lawrence
authors.affiliation: Melinta Therapeutics, Lincolnshire, Illinois. Electronic address: scammarata@melinta.com.
authors.forename: Sue
authors.initials: S
authors.lastname: Cammarata
authors.affiliation: Melinta Therapeutics, Lincolnshire, Illinois.
authors.forename: Eugene
authors.initials: E
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013607:Tablets; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D013607:Tablets; C477891:delafloxacin
keywords: bioavailability; delafloxacin; intravenous; pharmacokinetic properties; safety; tolerability