• Wolfgang W Wicha, Thomas C Marbury, James A Dowell, Jared L Crandon, Cathie Leister, James Ermer, and Steven P Gelone.
• Nabriva Therapeutics GmbH, Vienna, Austria.
• Pharmacotherapy. 2021 May 1; 41 (5): 457-462.

Study ObjectiveLefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that, lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects.DesignOpen-label, Phase-1 clinical pharmacokinetic study.SettingResearch Study Center.PatientsTwenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores.Measurements And Main ResultsSubjects were administered a single dose of IV lefamulin 150 mg over 1 h. Plasma was collected for 48 h and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in Cmax and increases in renal clearance for Moderate and Severe groups, as well as, the increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h.ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma-protein binding was seen in hepatically-impaired versus normal subjects.ConclusionLefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding.© 2021 Pharmacotherapy Publications, Inc.

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