Nachum Kaplan1, Colin Garner, Barry Hafkin. 1. Affinium Pharmaceuticals, Inc., 200 Front Street West, Suite 3004, P.O. Box 31, Toronto, ON M5V 3K2, Canada. Electronic address: nkaplan@afnm.com.
Abstract
OBJECTIVES: 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. METHODS: Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted. RESULTS: 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 [(14)C]-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 ∼7 h 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 [(14)C]-AFN-1252 following intravenous or oral administration. CONCLUSIONS: 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.
OBJECTIVES: 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. METHODS: Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted. RESULTS: 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 [(14)C]-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 ∼7 h 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 [(14)C]-AFN-1252 following intravenous or oral administration. CONCLUSIONS: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.
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