Pharmacokinetics and Safety of Lefamulin After Single Intravenous Dose Administration in Subjects with Impaired Renal Function and those Requiring Hemodialysis

STUDY OBJECTIVE Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed. DESIGN Open-label, Phase-1 pharmacokinetic study SETTING: Research Study Center PATIENTS: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 mL/min), eight with "Severe" renal impairment (glomerular filtration rate <30 mL/min/1.73 m2), and eight subjects requiring hemodialysis. MEASUREMENTS AND MAIN RESULTS Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On-dialysis), as well as, on a non-dialysis day (Off-dialysis). Plasma, urine, and dialysate fluid was collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during On- and Off-dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate. CONCLUSION No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.