Bone and Joint Tissue Penetration of the Staphylococcus-Selective Antibiotic Afabicin in Patients Undergoing Elective Hip Replacement Surgery

Abstract

Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono (Debio 1452, AFN-1252), a novel antibiotic in development which targets the staphylococcal enoyl-acyl carrier protein reductase (FabI) and exhibits selective potent antibacterial activity against staphylococcal species, including methicillin-resistant Staphylococcus aureus As part of clinical development in bone and joint infections, a distribution study in bone was performed in 17 patients who underwent elective hip replacement surgery. Patients received 3 doses of 240 mg afabicin orally (every 12 h) at various time points before surgery. Afabicin desphosphono concentrations were measured by liquid chromatography-tandem mass spectrometry in plasma, cortical bone, cancellous bone, bone marrow, soft tissue, and synovial fluid collected during surgery at 2, 4, 6, or 12 h after the third afabicin dose. The study showed good penetration of afabicin desphosphono into bone tissues, with mean area under the curve ratios for cortical bone-, cancellous bone-, bone marrow-, soft tissue-, and synovial fluid-to-total plasma concentrations of 0.21, 0.40, 0.32, 0.35, and 0.61, respectively. When accounting for the free fraction in plasma (2%) and synovial fluid (9.4%), the mean ratio was 2.88, which is indicative of excellent penetration and which showed that the afabicin desphosphono concentration was beyond the MIC90 of S. aureus over the complete dosing interval. These findings, along with preclinical efficacy data, clinical efficacy data for skin and soft tissue staphylococcal infection, the availability of both intravenous and oral formulations, and potential advantages over broad-spectrum antibiotics for the treatment of staphylococcal bone or joint infections, support the clinical development of afabicin for bone and joint infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02726438.).

Keywords: Debio 1450; Staphylococcus aureus; afabicin; drug development; drug penetration; joint infections; osteomyelitis; pharmacokinetics.

Copyright © 2019 Menetrey et al.

Figures

FIG 1

Profile of the afabicin desphosphono concentration in plasma after the third oral dose of afabicin (240 mg, q12h) in patients undergoing hip replacement surgery. The results are presented as the geometric mean ± SD obtained using data from nominal time points (number of patients = 14).

FIG 2

Individual afabicin desphosphono concentrations in plasma (A), cortical bone (B), cancellous bone (C), synovial fluid (D), bone marrow (E), and soft tissue (F) after the third oral dose of afabicin (240 mg, q12h) in patients undergoing hip replacement surgery. Data are from 14 patients, with the following exceptions: for 1 patient, the plasma sample was missing at the time of resection and the plasma concentration was extrapolated by linear regression between the two adjacent concentration data from the full PK profile in plasma. Synovial fluid was obtained for 8 patients only. For one patient no results except for plasma were reportable at the time of resection, and for another, only plasma, soft tissue, and bone marrow were collected at the time of resection.

FIG 3

Osteoarticular tissue- and fluid-to-plasma concentration ratios obtained for vancomycin, linezolid, ertapenem, daptomycin, dalbavancin, and afabicin. Mean ratios (median ratios for ertapenem) were obtained from published data from studies with designs similar to that of this study, i.e., dosing in patients undergoing elective replacement surgery and analysis of the total concentration of the drugs in homogenized bone tissues or synovial fluid collected during surgery (20–25) at steady state for linezolid and afabicin and after a single dose for the other antibiotics. Vancomycin, linezolid, and ertapenem were quantified in serum, whereas daptomycin, dalbavancin, and afabicin desphosphono were quantified in plasma.