Metabolism, Excretion and Mass Balance of Solithromycin in Humans [PublishAheadOfPrint]

Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin, were studied in healthy male subjects after oral administration of a single 800 mg (~100 μCi) dose of [¹⁴C]solithromycin. Solithromycin was well tolerated and absorption from the solution occurred with a median time to peak concentration of 4.0 hours. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole blood total radioactivity was approximately 75% of plasma total radioactivity. Recovery was essentially complete (mean 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity AUC) with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly as parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.

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