Clinical Pharmacokinetics of Sulfobutylether-β-Cyclodextrin in Patients With Varying Degrees of Renal Impairment

Abstract

Delafloxacin, a fluoroquinolone, has activity against Gram-positive organisms including methicillin-resistant S aureus and fluoroquinolone-susceptible and -resistant Gram-negative organisms. The intravenous formulation of delafloxacin contains the excipient sulfobutylether-β-cyclodextrin (SBECD), which is eliminated by renal filtration. This study examined the pharmacokinetics and safety of SBECD after single intravenous (IV) infusions in subjects with renal impairment. The study was an open-label, parallel-group, crossover study in subjects with normal renal function or mild, moderate, or severe renal impairment, and those with end-stage renal disease undergoing hemodialysis. Subjects received 300 mg delafloxacin IV or placebo IV, containing 2400 mg SBECD, in 2 periods separated by ≥14-day washouts. SBECD total clearance decreased with decreasing renal function, with a corresponding increase in area under the concentration-time curve (AUC_0-∞ ). After IV delafloxacin 300 mg administration, SBECD mean total clearance was 6.28 and 1.24 L/h, mean AUC_0-∞ was 387 and 2130 h·μg/mL, and mean renal clearance was 5.36 and 1.14 L/h in normal and severe renal subjects, respectively. Similar values were obtained after IV placebo administration. In subjects with end-stage renal disease, delafloxacin 300 mg IV produced mean SBECD AUC_0-48 values of 2715 and 7861 h·μg/mL when dosed before and after hemodialysis, respectively. Total SBECD clearance exhibited linear relationships to estimated glomerular filtration rate and creatinine clearance. Single doses of IV delafloxacin 300 mg and IV placebo were well tolerated in all groups. In conclusion, decreasing renal function causes reduced SBECD clearance and increased exposures, but SBECD continues to exhibit a good safety and tolerability profile in IV formulations.

Keywords: Delafloxacin; Hemodialysis; Pharmacokinetics; Renal Dysfunction; Sulfobutylether-β-cyclodextrin.

Figure 1

Mean (SD) plasma concentration‐time profiles in subjects with varying degrees of renal function after IV infusion of 2400 mg SBECD from either 300 mg IV delafloxacin (panels A and B) or IV placebo (panels C and D). Upper panels (A and C), linear scale. Lower panels (B and D), semi‐log scale. IV indicates intravenous; SBECD, sulfobutylether‐β‐cyclodextrin.

Figure 2

Cumulative mean urinary excretion (A_e) of SBECD in subjects with varying degrees of renal function after IV dosing of 2400 mg SBECD from either 300 mg IV delafloxacin (A) or IV placebo (B). IV indicates intravenous; SBECD, sulfobutylether‐β‐cyclodextrin.

Figure 3

AUC_inf vs eGFR after IV dosing of 2400 mg SBECD from either 300 mg IV delafloxacin (A) or IV placebo (B). Solid lines are hyperbolic line regressions. AUC_inf indicates area under the concentration‐time curve to infinity; eGFR, estimated glomerular filtration rate; IV, intravenous; SBECD, sulfobutylether‐β‐cyclodextrin.

Figure 4

Linear regression of total clearance vs eGFR after IV dosing of 2400 mg SBECD from either 300 mg IV delafloxacin (A) or IV placebo (B). Solid lines are linear regressions of total clearance vs eGFR; dashed lines are the 95%CIs of the linear regressions. CL_tot indicates total clearance; eGFR, estimated glomerular filtration rate; IV, intravenous; SBECD, sulfobutylether‐β‐cyclodextrin.

Figure 5

Mean (SD) plasma concentration‐time profiles in ESRD subjects after IV infusion of 2400 mg SBECD from 300 mg IV delafloxacin either before or after hemodialysis. A, Linear scale. B, Semi‐log scale. ESRD indicates end‐stage renal disease; IV, intravenous; SBECD, sulfobutylether‐β‐cyclodextrin.