Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function

Abstract

Delafloxacin, a fluoroquinolone, has activity against gram-positive organisms including methicillin-resistant Staphylococcus aureus and fluoroquinolone-susceptible and -resistant gram-negative organisms. This study was conducted to determine delafloxacin pharmacokinetics after a single intravenous infusion or oral dose administration in subjects with varying degrees of renal function. The study was an open-label, parallel-group crossover study in subjects with normal renal function or with mild, moderate, or severe renal impairment. Subjects received 300 mg delafloxacin intravenously, placebo intravenously, and 400 mg delafloxacin orally in 3 periods separated by ≥14-day washouts. Blood and urine pharmacokinetic parameters were calculated using noncompartmental methods. Delafloxacin total clearance decreased with decreasing renal function, with a corresponding increase in AUC_0-∞ . After intravenous administration, mean total clearance was 13.7 and 7.07 L/h, and mean AUC_0-∞ was 22.6 and 45.0 μg·h/mL in normal and severe renal subjects, respectively. Mean renal clearance as determined by urinary excretion was 6.03 and 0.44 L/h in normal and severe renal impairment subjects, respectively. Total clearance exhibited linear relationships to eGFR and CL_CR . Similar observations were found after oral administration of delafloxacin. Single doses of delafloxacin 300 mg intravenously and 400 mg orally were well tolerated in all groups. In conclusion, renal insufficiency has an effect on delafloxacin clearance; a dosing adjustment for intravenous dosing is warranted for patients with severe renal impairment (eGFR < 30 mL/min).

Keywords: delafloxacin; fluoroquinolones; pharmacokinetics; renal dysfunction.

Figure 1

Mean plasma concentration–time profiles in subjects with varying degrees of renal function after either intravenous infusion of 300 mg of delafloxacin (A) or oral administration of 400 mg of delafloxacin (B).

Figure 2

Cumulative mean urinary excretion (A_e) of delafloxacin in subjects with varying degrees of renal function after either intravenous infusion of 300 mg of delafloxacin (A) or oral administration of 400 mg of delafloxacin (B).

Figure 3

Linear regression of total clearance (/F) versus eGFR after either 300 mg intravenous delafloxacin (A) or 400 mg delafloxacin orally (B). Solid lines are linear regressions of total clearance versus eGFR; dashed lines are the 95% confidence intervals of the linear regressions.