Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Randall Hoover, Thomas C Marbury, Richard A Preston, Megan Quintas, Laura E Lawrence, Susan K Paulson, David R Luke, Sue K Cammarata, Randall Hoover, Thomas C Marbury, Richard A Preston, Megan Quintas, Laura E Lawrence, Susan K Paulson, David R Luke, Sue K Cammarata

Abstract

Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram-positive, Gram-negative, atypical, and anaerobic bacteria, including methicillin-resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia. This was a phase 1, open-label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log-transformed values for AUC0-∞ , Cmax , and systemic clearance, with hepatic group as a fixed effect. Mean AUC0-∞ and Cmax in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least-squares means of AUC0-∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child-Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child-Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child-Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed.

Trial registration: ClinicalTrials.gov NCT02245243.

Keywords: delafloxacin; fluoroquinolones; hepatic impairment; pharmacokinetics.

© 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean (± SD) plasma concentrations of delafloxacin (μg/mL) vs time profiles by hepatic group: group A mild (●), group B moderate (♦), group C severe (■), and pooled matched controls (◊).
Figure 2
Figure 2
Box‐and‐whisker plots of mean delafloxacin AUC0‐∞, Cmax, CL, and Vss values by hepatic function. The whiskers represent the 5th and 95th percentiles.

References

    1. Bassetti M, Della Siega P, Pecori D, Scarparo C, Righi E. Delafloxacin for the treatment of respiratory and skin infections. Expert Opin Investig Drugs. 2015;24:433–442.
    1. Van Bambeke F. Delafloxacin, a non‐zwitterionic fluoroquinolone in phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics, and clinical efficacy. Future Microbiol. 2015;10:1111–1123.
    1. Hoover R, Hunt T, Benedict M, et al. Safety, tolerability, and pharmacokinetic properties of intravenous delafloxacin after single and multiple doses in healthy volunteers. Clin Ther. 2016;38:53–65.
    1. Hoover R, Hunt T, Benedict M, et al. Single and multiple ascending‐dose studies of oral delafloxacin: effects of food, sex, and age. Clin Ther. 2016;38:39–52.
    1. Hoover R, Lawrence L, Benedict M, et al. Pharmacokinetics and relative bioavailability of intravenous and oral formulations of delafloxacin (DLX) in healthy subjects [poster]. Presented at Interscience Conference of Antimicrobial Agents and Chemotherapy; September 5, 2014; Washington, DC.
    1. McEwen A, Lawrence L, Hoover R, et al. Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration. Xenobiotica. 2015;45:1054–1062.
    1. O'Riordan W, Mehra P, Manos P, Kingsley J, Lawrence L, Cammarata S. A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin‐structure infections. Int J Infect Dis. 2015;30:67–73.
    1. Kingsley J, Mehra P, Lawrence LE, et al. A randomized, double‐blind, phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin. J Antimicrob Chemother. 2016;71:821–829.
    1. Cammarata S, Gardovskis J, Farley B, et al. Results of a global phase 3 study of delafloxacin (DLX) compared to vancomycin with aztreonam (VAN) in acute bacterial skin and skin structure infections (ABSSSI). Presented at IDWeek; October 7, 2015; San Diego, CA.
    1. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85.
    1. Pugh RN, Murray‐Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646–649.
    1. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics‐pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis. 2007;44:79–86.
    1. King CD, Rios GR, Green MD, Tephly TR. UDP‐glucuronosyltransferases. Curr Drug Metab. 2000;1:143–161.
    1. Pacifici GM, Viani A, Franchi M, et al. Conjugation pathways in liver disease. Br J Clin Pharmacol. 1990;30:427–435.
    1. Yeung CK, Yoshida K, Kusama M, et al. Organ impairment—drug‐drug interaction database: A tool for evaluating the impact of renal or hepatic impairment and pharmacologic inhibition on the systemic exposure of drugs. CPT Pharmacometr Syst Pharmacol. 2015;4:489–494.
    1. Lawrence L, Quintas M, Hoover R, et al. A phase 1, open‐label study of the effect of delafloxacin (DLX) on the pharmacokinetics (PK) of a single oral dose of midazolam (MID). Presented at the American Society for Microbiology, Microbe 2016; June 16, 2016; Boston, MA.
    1. . Accessed May 18, 2016.
    1. Keller F, Maiga M, Neumayer HH, Lode H, Distler A. Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease. Eur J Drug Metab Pharmacokinet. 1984;9:275–282.

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