Mass Balance, Pharmacokinetics and Metabolism of the Antimicrobial Afabicin Following Intravenous and Oral Administration in Humans

Abstract

Debio1450 (afabicin) is a novel antimicrobial with potent and selective activity against staphylococci including MRSA. As part of the development of IV and PO formulations, a human ADME study was performed after IV and oral administration of [14C-pos1]-Debio1450, as well as after oral administration of a [14C-pos25]-Debio1450 microtracer to ensure a complete tracking of the metabolites. Three groups of 6 healthy male subjects received either 240 mg [14C-pos1]-Debio1450 (3.7-4.8 MBq) IV or PO, or 240 mg [14C-pos25]-Debio1450 (0.37 MBq) PO. Total radioactivity was assessed in plasma, blood, expired air, urine and feces using either conventional methods or AMS. Prodrug Debio1450 and active moiety Debio1452 were quantified in plasma and urine using validated LC-MS/MS methods. The metabolite profiles were determined using HPLC-UPLC with off-line radio-detection (Topcount or AMS). Metabolites were characterised using HRMS. Pharmacokinetic analysis was conducted by non-compartmental methods. The ADME profile of [14C]-Debio1450 showed no relevant difference between PO and IV routes, except for circulating levels of Debio1450 observed after IV administration only. Debio1450 was very rapidly converted into Debio1452, even pre-systematically after oral administration. Systemic exposure to Debio1452 accounted for at least 32% of total radioactivity in plasma, with an apparent oral bioavailability of ~0.7 and a half-life of 8.4-11.3 hours. Two major metabolites were identified in plasma, with no antimicrobial activity, and no disproportionality when compared to exposures in animal species. The total excreted radioactivity was 87.4-94.8%, with 51-68% in the urine and 27-37% in the feces, and with Debio1452 constituting less than 0.05% and 3% of the total radioactivity, respectively. Debio1450 demonstrated a favorable and similar ADME profile after single PO and IV administrations of [14C]-Debio1450, with rapid conversion into the active moiety Debio1452 and a bioavailability of 0.7, supporting an IV to PO switch during Debio1450 treatment of staphylococcal infections.