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.).

A method for studies on interactions between a gold-based drug and plasma proteins based on capillary electrophoresis with inductively coupled plasma mass spectrometry detection.

An analytical method based on capillary electrophoresis (CE) and inductively coupled plasma mass spectrometry (ICP-MS) detection was developed for studies on the interaction of gold-containing drugs and plasma proteins using auranofin as example. A detection limit of 18 ng/mL of auranofin corresponding to 5.2 ng/mL Au and a precision of 1.5 % were obtained. Kinetic studies of the interaction between auranofin and protein were performed by incubation in aqueous solutions as well as 20 % human plasma at 37 °C. The reaction of auranofin with human serum albumin (HSA) and plasma proceeded fast; 50 % of un-bound auranofin disappeared within 2 and 3 min, respectively. By blocking the free cysteine (Cys-34) by iodoacetamide on HSA, it was shown that Cys-34 was the main reaction site for auranofin. By selective labeling of HSA present in 20 % human plasma with iophenoxate, it was demonstrated that HSA was the major auranofin-interacting protein in plasma. The CE-ICP-MS method is proposed as a novel approach for kinetic studies of the interactions between gold-based drugs and plasma proteins. Graphical Abstract Development of a CE-ICP-MS based method allows for studies on interaction of the gold containing drug auranofin with plasma proteins.

Dicyanogold (I) is a common human metabolite of different gold drugs.

Gold based drugs and their metabolites have been characterized using reversed phase, ion pairing chromatography with an inductively coupled plasma mass spectrometer as an element specific detector. For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking auranofin and in patients taking solganol. This represents the first identification of a specific gold metabolite in biological fluids taken from patients undergoing gold therapy and the first evidence that different gold drugs have common metabolites.

Pharmacokinetics of auranofin a single dose study in man.

Three days after cholecystectomy 7 patients were given a single dose of auranofin (5 tablets Ridaura = 4.35 mg gold). Gold was detected in samples of blood, plasma, urine, bile and feces. The determinations were carried out using instrumental neutron activation analysis. The mean gold concentrations reached maximum in blood and plasma after 2 h and in urine and bile after 16 h. The mean terminal half-lives were 7.6 days (blood), 15 days (plasma) and 6.5 days (bile). Cumulative amounts of gold excreted in bile, urine, and feces were 1.6, 4 and 40%, respectively.

Auranofin therapy in juvenile rheumatoid arthritis: a 48-week phase II study.

A 48-week phase II open, uncontrolled study of auranofin (AF) in patients juvenile rheumatoid arthritis (JRA) was conducted to assess efficacy, tolerance and serum gold levels, and to consider the feasibility of further controlled studies (phase III) in such patients. The study group included 25 patients (20 F, 5 M) with active pauciarticular (n = 4) or polyarticular (n = 21) JRA. Median age was 100 months (range 62-176); median disease duration was 55 months (range 13-155). AF was given at 0.1 mg/kg/day divided into 2 doses, and increases to maximum of 6 mg/day were permitted if clinical improvement was insufficient. Nonsteroidal anti-inflammatory drugs and physiotherapy also were allowed. Significant improvement (p less than or equal to 0.05) was observed in the various joint counts and articular indices, as well as in the physician's global assessment of health. Some subjective functional measurements also were improved, but the differences were not statistically significant. There were no clinically important trends in the laboratory measurements. No patient was withdrawn because of adverse reactions; 1 was withdrawn because of disease exacerbation and 3 for lack of response. Mild adverse reactions were seen in 9 patients: 6 had abdominal pain, 6 diarrhea/loose stools, 1 nausea, 3 rash, 2 pruritus. Two patients had dosage reduced because of loose stools. Serum gold levels varied greatly; increased dosage usually resulted in increased serum levels. Occurrence of adverse reactions or response to therapy was not related to increases in dose or to serum gold levels.(ABSTRACT TRUNCATED AT 250 WORDS)