Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function

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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 ). After IV delafloxacin 300 mg administration, SBECD mean total clearance was 6.28 and 1.24 L/h, mean AUC 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 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.

Section: Safety Assessmentsmentioning

confidence: 99%

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confidence: 92%

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confidence: 99%

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

Hoover¹,

Alcorn

Lawrence

et al. 2018

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“…Details of the study design have been previously reported as well as the pharmacokinetic and safety/tolerability results from subjects with mild, moderate, and severe impairment compared to subjects with normal renal function. 7,8 The subjects with ESRD participated in 2 treatment periods that were separated by a washout period of at least 14 days. Subjects were administered a 1-hour IV infusion of 300 mg delafloxacin approximately 1 hour before initiation of hemodialysis (period 1) or after completion (period 2) of the last hemodialysis session of the week.…”

Section: Methodsmentioning

confidence: 99%

“…6 A study of the effect of mild, moderate, and severe renal impairment on the pharmacokinetics (PK) of a single dose of IV and oral delafloxacin showed that delafloxacin total clearance decreased as the degree of renal function worsened. 7,8 Renal clearance of delafloxacin in severe impairment was 0.44 L/h compared to 6.03 L/h in subjects with normal renal function. Delafloxacin total exposure expressed as area under the plasma concentration-time curve (AUC) in severely renal-impaired subjects was approximately twice that of those with normal renal function regardless of route (IV or oral) of administration, with maximum exposure (C max ) being similar across the renal function groups (mild, moderate, and severe).…”

mentioning

confidence: 98%

Pharmacokinetics of Intravenous Delafloxacin in Patients With End‐Stage Renal Disease

Hoover¹,

Alcorn

Lawrence

et al. 2018

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This was an open-label, parallel-group, crossover study that examined the pharmacokinetics and safety of delafloxacin, an anionic fluoroquinolone, after a single intravenous infusion in subjects with end-stage renal disease (ESRD; creatinine clearance <15 mL/min) undergoing hemodialysis compared with healthy subjects. Subjects received 300 mg delafloxacin containing sulfobutylether-β-cyclodextrin in 2 periods separated by ≥14-day washouts. Blood and urine samples were collected, and pharmacokinetic parameters were calculated using noncompartmental methods. The mean total exposure (area under the curve) of delafloxacin was about 2.1 and 2.6 higher for subjects with ESRD compared to healthy subjects when dosed 1 hour before or 1 hour after hemodialysis, respectively. Compared to subjects with normal renal function, the maximum exposure to delafloxacin was 13% and 33% higher for ESRD subjects given delafloxacin 1 hour before and 1 hour after hemodialysis, respectively. The mean clearance was 13.7 L/h for healthy subjects and was lower for subjects with ESRD when given before (7.39 L/h) or after (5.69 L/h) hemodialysis. The clearance of delafloxacin in dialysate was 4.74 L/h with about 19.2% of the delafloxacin dose recovered after a 4-hour dialysis session. Delafloxacin was well tolerated in both healthy and ESRD subjects, with diarrhea being the most reported treatment-emergent adverse event.

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Crass

Pai

2018

Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.