Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 1
• Main Authors: Capparelli, Edmund V, Bricker-Ford, Robin, Rogers, M John, McKerrow, James H, Reed, Sharon L
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.01.2017
• Subjects: Administration, Oral; Adult; Antiparasitic Agents; Antiparasitic Agents - blood; Antiparasitic Agents - pharmacokinetics; Antirheumatic Agents; Antirheumatic Agents - blood; Antirheumatic Agents - pharmacokinetics; Auranofin; Auranofin - blood; Auranofin - pharmacokinetics; Computer Simulation; Drug Administration Schedule; Drug Dosage Calculations; Drug Repositioning; Entamoeba histolytica; Entamoeba histolytica - drug effects; Entamoeba histolytica - growth & development; Experimental Therapeutics; Female; Giardia; Giardia intestinalis; Giardia lamblia; Giardia lamblia - drug effects; Giardia lamblia - growth & development; Gold - blood; Half-Life; Healthy Volunteers; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Male; Metronidazole - pharmacology; Models, Statistical; Tissue Distribution; antiparasitic agents; auranofin; phase I trial
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.01947-16

Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (C ) at day 7 was 0.312 μg/ml and the half-life (t ) 35 days, so steady-state blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 μM (auranofin equivalent), or more than 25× the 50% inhibitory concentration (IC ) for E. histolytica and 4× that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 μg/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broad-spectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.).