705. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Renal Function and in Those Requiring Hemodialysis

Abstract

BackgroundRenal comorbidities are common in patients hospitalized with community-acquired bacterial pneumonia (CABP). LEF, a novel pleuromutilin antibiotic (IV/oral), was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with severe renal impairment and those requiring hemodialysis (HD).MethodsIn this open-label study, subjects were allocated to 1 of 3 groups based on renal function level. Severe subjects (estimated glomerular filtration rate <30 mL/minute/1.73 m2, not on HD, Severe) were matched (gender, age, and weight) to subjects with normal renal function (estimated creatinine clearance ≥90 mL/minute, Normal). Subjects in the Normal and Severe groups received a single 1-hour 150 mg LEF infusion. Subjects in the HD group started HD within 1 hour after LEF infusion (“On-dialysis”) and on a nondialysis day (“Off-dialysis”). Blood and urine samples were collected predose and over a 36-hour period postdose for PK analysis; LEF and BC-8041 were assayed in plasma and urine with validated methods. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.Results23 subjects enrolled in and completed the study (n = 7, Normal; n = 8, Severe; n = 8, HD). LEF and BC-8041 pharmacokinetic parameters (table) were comparable between the Normal and Severe groups and between the On-dialysis and Off-dialysis treatment periods for the HD group. The majority of LEF and BC-8041 were excreted nonrenally in Normal and Severe subjects and were not measurably filtered into dialysate. TEAEs were reported in 2 (28.6%) subjects in the Normal group, 4 (50%) in the Severe group, and 4 (50%) in the HD group. None of the TEAEs were serious or led to study drug discontinuation. Within 4 h post-dose, the maximum mean change from baseline in the QTcF interval was 8.9, 6.6, 15.9, and 17.6 msec in the normal, severe, on-dialysis, and off-dialysis groups, respectively.ConclusionNo dosage adjustment is required for LEF when treating subjects with severe renal impairment, and LEF can be administered without regard to HD timing. LEF was generally well tolerated in all subjects regardless of renal function status. Disclosures All authors: No reported disclosures.