Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent.
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 (Cmax) at day 7 was 0.312 μg/ml and the half-life (t1/2) 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 (IC50) 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.).
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
Edmund V
EV
Capparelli
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
Robin
R
Bricker-Ford
Division of Microbiology and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
M John
MJ
Rogers
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
James H
JH
McKerrow
Departments of Pathology and Medicine, University of California, San Diego, School of Medicine, La Jolla, California, USA slreed@ucsd.edu.
Sharon L
SL
Reed
D000284:Administration, Oral; D000328:Adult; D000977:Antiparasitic Agents / Q000097:blood / Q000493:pharmacokinetics*; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001310:Auranofin / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D058492:Drug Repositioning; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000254:growth & development; D005260:Female; D016829:Giardia lamblia / Q000187:drug effects* / Q000254:growth & development; D006046:Gold / Q000097:blood; D006207:Half-Life; D064368:Healthy Volunteers; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D015233:Models, Statistical; D014018:Tissue Distribution
D000977:Antiparasitic Agents; D018501:Antirheumatic Agents; D008795:Metronidazole; D001310:Auranofin; D006046:Gold
antiparasitic agents; auranofin; phase I trial