AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects

• Published in: European journal of pharmaceutical sciences Vol. 50; no. 3-4; pp. 440 - 446
• Main Authors: Kaplan, Nachum, Garner, Colin, Hafkin, Barry
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 20.11.2013
• Subjects: Absorption; ADME; Adolescent; Adult; AFN-1252; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - urine; Benzofurans - administration & dosage; Benzofurans - blood; Benzofurans - pharmacokinetics; Benzofurans - urine; Blister - metabolism; Caco-2 Cells; Cross-Over Studies; Dose-Response Relationship, Drug; FabI inhibitor; Feces - chemistry; Humans; Intestines - metabolism; Male; Middle Aged; Phase 0; Plasma - chemistry; Pyrones - administration & dosage; Pyrones - blood; Pyrones - pharmacokinetics; Pyrones - urine; Rats; Rats, Sprague-Dawley; Staphylococcus aureus; Young Adult; AFN-1252; FabI inhibitor; Phase 0; ADME; Staphylococcus aureus
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2013.08.019

[Display omitted] To investigate the absorption, distribution, metabolism and excretion of AFN-1252, a novel inhibitor of the essential FabI enzyme in Staphylococcus spp., in vitro and following microdosing in healthy adult male subjects following intravenous and oral administration. Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted. The Caco-2 assay indicated that AFN-1252 in solution is well-absorbed and undergoes insignificant efflux, and its transport across the intestinal wall is probably passive. In the rat intestinal perfusion model, AFN-1252 exhibited high permeability potential across three segments, in the rank order of jejunum=ileum>colon. Taken together with the low aqueous solubility, the data from these studies indicate that AFN-1252 is a BCS Class II molecule with solubility-limited absorption. Analysis of the [14C]-AFN-1252 radioactivity concentration–time data indicated similar pharmacokinetics following intravenous and oral administration in the microdosing study in healthy volunteers. These included long terminal half-lives of ∼7h and 83% bioavailability, indicating that there was little first-pass metabolism following oral dosing. AFN-1252 exhibited good distribution to skin and skin structures where its anti-staphylococcal activity may be required. Urinary and faecal excretion are major elimination routes for [14C]-AFN-1252 following intravenous or oral administration. AFN-1252 has the potential for both intravenous and oral administration, once- or twice-daily dosing and good tissue distribution in humans. Further safety, efficacy and pharmacokinetic studies in man are required to investigate therapeutically-relevant doses for this novel agent and its targeted selectivity and high potency against Staphylococcus spp.