Auranofin: A Unique Oral Chrysotherapeutic Agent

By R. C. Blodgett, Jr., M. A. Heuer, and R. G. Pietrusko

OLD has been used for the treatment of S[triethylphosphine] gold. In this coordination G disease in humans since the early days of complex, a central atom of gold (I) is stabilized civilization. Its use in rheumatoid arthritis (RA) by phosphine and thiolate ligands. The unique may have had its genesis when Robert Koch structure of auranofin (Fig. 1) has been con- evaluated gold cyanide gas for inhibiting the firmed by crystal roentgenogram diffraction growth of tuberculosis bacilli.’ In 1927, Lande study and Mossbauer spectroscopy.‘3.‘4 Aurano- reported on the use of aurothioglucose for bacte- fin contains 29% gold by weight. rial endocarditis and other conditions probably Since phosphine is not a bridging ligand, aura- including rheumatic fever.2X3He made special nofin exists in a monomeric form which may note of joint pain relief and suggested that a trial contribute to its oral absorption. Previously, it of gold compounds in painful arthritis might be was believed that GST and aurothioglucose also useful. In 1929, Forestier, the “Father of Gold existed in monomeric forms. However, sophisti- Therapy,” referred to the work of Lande and cated synchrotron radiation evaluation has dem- Pick in his presentation to the Medical Society of onstrated that both these parenteral compounds Paris Hospitals. 46 He surmised that if gold was must be polymeric (or oligomeric) in nature.15 useful for chronic illness such as tuberculosis, it In contrast to injectable gold formulations, seemed worthwhile to test its activity in RA. auranofin is highly lipid-soluble, possesses only a Over the next 50 years, numerous studies were slight net charge in solution, and does not react published and a few noteworthy placebo-con- strongly with sulfhydryl groups.‘0,‘6*‘7 These trolled, double-blind studies confirmed the effi- properties may facilitate the transport of aurano- cacy of gold in the management of RA.7m9When fin across biologic membranes, making it more Sutton and coworkers reported their findings on readily available to alter cellular processes.‘7,‘8 an oral gold compound with antiarthritic activity When comparing auranofin to the currently in 1972, progress was made in the history of available parenteral gold products, it is impor- chrysotherapy.“’ tant to note that the activity of a gold compound is not determined solely by the presence of the HISTORY OF AURANOFIN metal itself. Changes in oxidation state, degree of Based upon the hypothesis that an orally polymerization, types of ligands, and geometric absorbed gold compound administered in a low, structure of the molecule can dramatically alter but therapeutic dose might offer a separation of biologic properties ranging from pharmacokine- efficacy from toxicity, numerous compounds tics to physiologic activity.” The importance of were screened and evaluated. In the intense the coordination complex surrounding the heavy search for such agents, 13 alkylphosphine gold metal has been demonstrated with another tran- coordination complexes showed antiarthritic sition metal, platinum. Cis-diamine dichlorpla- activity when administered orally to adjuvant tinum (II) is a highly active antitumor agent but arthritic rats.” One of the most potent com- the trans isomer exhibits no significant in vivo pounds evaluated was auranofin. Oral adminis- antitumor effect.*’ tration to laboratory animals suggested that its antiarthritic potency was similar to parenteral From the Department of Clinical Research & Develop- administration of gold sodium thiomalate ment, Smith Kline & French Laboratories, Philadelphia, (GST).” Since these original findings were PA. reported over 10 years ago, more than 3,000 Randolph C. Blodgett, Jr., M.D., F.A.C.P., Vice Presi- dent; Marvin A. Heuer, M.D., Associate Group Director; patients have been enrolled in worldwide studies Robert G. Pietrusko, Pharm.D., Senior Investigator. evaluating auranofin.12 Address reprint requests to Randolph C. Blodgett. Jr.. M.D., Clinical Research & Development, Smith Kline & CHEMISTRY French Laboratories, 1500 Spring Garden Street, P.O. Box 7929, Philadelphia, PA I91 OI. The chemical name for auranofin is 2,3,4,6- 0 1984 by Grune & Stratton, Inc. tetra-O-acetyl-l-thio-B-D-glucopyranosato- 0049~172/84/l303-0004$2.00/0

Seminars in Arthritis and Rheumarism, Vol. 13, No. 3 (February), 1984 255 BLODGElT, HEUER, AND PIETRUSKO

0.3 -

0.1 -

0.1 -

2 3 4 5 6 0-$-CH2 UOWIIIS 0 Fig. 2. The dose of auranofin versus steady state blood (2,3,4,6-Tetra-O-Acetyl-l-Thio-B-D-Glucopyranosato-S) gold levels: (0) patients receiving g mg per day, (ml (Mathylphospine) Gold patients receiving 6 mg per day, (0) patients receiving 2 mg per day, and (0) patients receiving 1 mg per day. Fig. 1. The structure of euranofin.

auranofin is expressed in terms of body weight PHARMACOKINETICS (mg/kg/day), there is a highly significant corre- Absorption lation with serum concentrations of gold.27 Absorption of auranofin is rapid, although Whether or not auranofin undergoes gastroin- incomplete. In six healthy young adult volunteers testinal alteration prior to being absorbed has not receiving a single 6 mg oral dose of auranofin, an been determined. Weisman et al. have proposed average peak blood gold level of 0.025 mcg/ml the following two theories based upon their intes- was observed at two hours.” Peak blood levels tinal perfusion studies with radiolabeled marker: ranged from 0.014 to 0.046 mcg/ml and (1) auranofin is loosely and reversibly adsorbed occurred from one to 72 hours after administra- onto the surface of small bowel mucosal cells tion. Administration of a dilute alcohol solution with subsequent elution of the gold downstream containing 6 mg of radiolabeled “‘Au-auranofin into the intestinal fluid, and (2) this compound is to six patients with RA produced a peak concen- absorbed into the enterocyte, the carrier tration of 0.066 mcg/ml within 1.2 to two hours removed, and a large portion of the elemental after administration.22 The fraction of oral gold reexcreted into the lumen.3’ absorption of gold from auranofin was estimated Although the effect of food on the bioavaila- to range from a minimum of 15% to a maximum bility of auranofin has not been evaluated, in of 33% in this study. Predictions based upon a vitro analysis indicates that auranofin is stable in complex multi-compartmental pharmacokinetic buffered Sustacal@ for up to three hours when model indicated that approximately 25% of the the pH is in the range of 1.O to 8.0.” gold contained in auranofin is absorbed. Initial clinical trials showed that auranofin is Distribution absorbed and continued use provides relatively Auranofin is associated with both cellular constant blood gold levels.23-25Analysis of blood components and plasma proteins when absorbed. gold concentrations in patients receiving aurano- In seven patients receiving auranofin for one fin shows a consistent proportional relationship month, an average of 41% of auranofin was between the oral dose and steady-state blood gold associated with red blood cells.32 Blood gold concentrations (Fig. 2). Data were derived from levels were equal to or exceeded serum gold levels patients receiving 1 to 9 mg auranofin per day for depending upon hematocrit. Radiolabeled ‘95Au- three or six months and from patients whose auranofin studies also indicated that 42% of dosage was increased after three months.26-30 blood gold was associated with cellular ele- Mean serum gold concentrations increase by ments.33 Of the approximately 40% fraction of approximately 0.1 mcg/ml for each increment of auranofin associated with erythrocytes, 37% is 1 mg in the daily dose of auranofin. This dose- intracellular and the remaining 3% is bound to blood level proportionality is maintained when the cell membrane.34 Negligible amounts of GST dosage is altered. When the daily dosage of bound to red blood cells or other cellular ele- AURANOFIN IN RA 257 ments were found in this study. Cigarette smok- gold containing ligands, triethylphosphine, and ing can increase the erythrocyte uptake of gold in thio-glucopyranose are without effect in the patients treated with GST but this effect has yet adjuvant arthritis rat mode1.46 to be evaluated with auranofin.3sV36Auranofin Radiolabeling of gold and the phosphorus and also possesses greater affinity for penetration of sulfur atoms of the ligand structures provides lymphocyte membranes as determined by carbon some insight into the metabolism of auranofin. rod atomization analysis3’ Approximately 1% or Dissociation of auranofin occurs within 20 min- less of auranofin is bound to other white blood utes after incubation with serum from the rat or cells and platelets. The significance of these dog.47 Much of the parent compound, however, findings is unclear but binding to cellular compo- may not reach the systemic circulation intact if nents may represent a biologic delivery system or in vivo dog studies, which demonstrate extensive serve as a reservoir of gold.32 The enhanced disruption of the coordination complex prior to membrane penetration observed may be related absorption, can be extended to humans.47 to the unique monomeric nature of auranofin3* Triethylphosphine oxide is a major metabolite Unbound serum gold may be responsible for renally excreted in the rat. This metabolite was the cellular effects of auranofin and other gold found in the urine in six patients with RA compounds. Preliminary evaluation indicates receiving auranofin 3 mg twice daily.*’ It was that the ratio of free or unbound serum gold to theorized that the auranohn molecule is cleaved total gold levels is greater for auranofin when to form triethylphosphine oxide, acetylthioglu- compared to GST.39 Synovial fluid penetration case, and a protein-gold complex, most likely occurs with auranofin. The synovial fluid/whole metallothionein.30*48 blood gold ratio was 1:l .740in 18 patients receiv- ing auranofin for 18 months. Blood Gold Levels and Elimination Half-Life The distribution of auranofin throughout the In the initial clinical trials, there was a pro- body is unknown. Animal data may provide some gressive increase in blood gold levels over a information since distribution of injectable gold period of 12 weeks in patients receiving 1 to 9 mg compounds in humans is generally similar to that auranofin each day.25,26Bandilla et al. observed observed in laboratory animals.4’s42Tissue gold steady state plasma levels at 12 weeks with no levels in the liver, kidney, and spleen of rats and further increase in gold levels for up to 24 months guinea pigs following GST administration were with continued therapy.” Other investigators 35-70 times higher than observed with aurano- have reported achievement of peak plasma levels fin.32*43Limited data in humans given GST by 10 to 16 weeks.49,50With attainment of steady showed that lymph nodes, adrenal glands, liver, state levels, minimal variation occurs in mean kidneys, bone marrow, and spleen have the high- blood gold levels during continuous daily admin- est concentrations of gold.44 Gold has also been istration of auranofin.24,27 The mean blood gold detected in other internal organs, including endo- level at steady state approximates 0.6 to 0.7 crine glands, muscle, and skin.4S The highest mcg/ml in those receiving auranofin 3 mg twice concentrations of auranohn in rats are found in a day.*‘,” decreasing order in the kidneys, spleen, adrenals, In six patients with RA given 6 mg of radiola- lungs, and liver. beled ‘95Au-auranofin prior to and six months In four patients whose total auranofin doses after daily auranofin, the mean plasma half-life ranged from 945 to 3,600 mg, gold was detected was approximately 17 days following the first in the skin biopsy of only one. Gold was found in dose and 25.5 days after the second dose.33 The all patients in concentrations ranging from 2.6 to mean terminal total body content half-life was 26.5 mcg/g tissue in similar skin biopsies per- calculated to be 58 and 81 days, respectively, formed in seven patients receiving GST in cumu- after the first and subsequent dose of radiola- lative doses of 460 to 4,325 mg.24 beled auranofin. In comparison, intramuscular GST generally Metabolism provides a peak blood gold concentration of 7 After auranofin is given, its fate within the mcg/ml the day of injection which gradually body is largely unknown. Gold appears to be declines to approximately 3 mcg/ml in one essential for antiarthritic activity since the non- week.24These levels are substantially higher than 258 BLODGETT, HEUER, AND PIETRUSKO observed with auranofin. The serum half-life of month evaluation. These findings are in marked GST ranges from five to six days and steady state contrast to the results obtained with parenteral levels are achieved in six to eight weeks.24V5’-s4 gold compounds. Using a similar technique, Ger- More of the total body burden of gold is retained ber et al. found that after injection of a single 50 than with auranofin (25%42% vs. < 1%) mg intravenous dose of GST, 25%-42% of the although the serum half-life of GST is shorter. administered dose remained in the body at six The correlation of serum gold levels with effi- months.” Approximately 70% of GST is elimi- cacy or safety during auranofin therapy remains nated in the urine and 30% is excreted in the to be established. Attainment of a serum level of feCes.45X61 0.7 mcg/ml was claimed in an open, uncontrolled Biliary excretion and enterohepatic recircula- study, to be associated with improvement in the tion of gold have not been observed with aurano- clinical parameters evaluated.26 In another open fin.2’,3’ Since biliary excretion is negligible, the trial, patients who responded had significantly nature of auranofin’s “central-enteric” excretory lower blood gold levels at 20 and 26 weeks than pathway must be further investigated.3s patients who exhibited no response.55 Other Table 1 summarizes the comparative pharma- investigators have found no convincing evidence cokinetic properties of auranofin and GST. that clinical improvement and/or toxicity are related to blood gold levels.56-59 PHARMACOLOGY Auranofin possesses antiinflammatory and Excretion antiarthritic properties although its exact mech- Initial reports of gold excretion patterns on anism of action in patients with RA is unknown. auranofin indicated that 95% of recoverable gold It can affect acute and chronic inflammatory was eliminated via the fecal route and 5% in the processes as well as cellular and immunopatho- urine.60 It was also estimated that after 20 weeks logic events involved in the perpetuation of of auranofin, approximately 27% of gold was inflammation and tissue damage (Table 2).62 retained in the body.24 These preliminary results Since it does not possess a general immunosup- provided only a general estimation of auranofin’s pressive action, auranofin has been referred to as elimination since methodologic problems includ- an immunoregulator.63 ing stool sampling design and a 10% variation in the analytical technique were evident. Animal Models of Injlammation With the use of a whole body radiation Analysis of in vivo models of inflammation in counting chamber, Blocka et al. found that laboratory animals suggests that auranofin in cumulative stool elimination of auranofin gold doses used is equal to or more effective than over six months was approximately 85% and GST. Kaolin and carrageenan-induced rat paw urinary excretion accounted for 15% of the edema was significantly reduced with aurano- dose.22 Total body retention of radiolabeled gold fin.62,64 Only modest inhibition of edema ranged from 0.4% to 1.3% at the end of the six occurred with GST and appeared to be partially . Table 1. Comparative Pharmacokinetics of Auranofin and Gold Sodium Thiomalate

Characteristic Auranofin GST

Oral absorption -25%

Table 2. Antiinflammatory and Immunologic Antiproliferative effects were observed in RAJI Profile of Auranofin lymphoma, HeLa carcinoma, and Epstein-Barr

Profile Effect virus-transformed cells.‘7~70Membrane transport

Animal model of inflammation inhibition was not observed in these studies how- Rat paw edema ever. It was hypothesized that the effects of UV light erythema auranofin on DNA, RNA, and protein synthesis Adjuvant arthritis (rat) may have been due to formation of a bond with Inflammatory cell function sulfhydryl groups of proteins associated with the Chemotaxis Phagocytosis mitotic process. Superoxide radical generation Chemotaxis of human monocytes, and to a Lysosomal enzyme release lesser extent neutrophils, is significantly im- Cell-mediated immunity paired by auranofin.” When monocytes of Oxazolone-induced delayed hyper- healthy donors were exposed to auranofin or gold sensitivity keratinate, chemotaxis was inhibited to a greater Lymphocyte transformation 1 Delayed hypersensitivity skin tests t.l,or- extent by auranofin.72 Inhibition of chemotaxis in Humoral immunity normal individuals or patients with RA however, Antibody-dependent cellular cytotox- was only slightly more pronounced with aurano- icity fin when compared to GST.73 Antibody-dependent complement ly- sis Phagocytic activity of macrophages is in- Circulating immunoglobulins creased in patients with RA but this process can

NOTE. ft) denotes enhanced effect, (1) denotes suppressed be suppressed to that of healthy individuals with effect; and f-b denotes no effect. the use of injectable gold salts.74l75Similar results were observed with auranofin when evaluated for adrenal dependent since its effects were more its effects on phagocytosis of IgG opsonized pronounced in nonadrenalectomized rats. Equiv- sheep RBCs, Candida albicans, and uptake of alent antierythemic effects were observed with nitroblue tetrazolium dye.72.73~76.77 auranofin and GST in guinea pigs exposed to Superoxide radicals (O,-) are products of the ultraviolet light; however, extremely large doses respiratory burst of activated phagocytic cells (100 mg/kg) of GST were necessary.64 The and are considered to be mediators of inflamma- effect of auranofin was observed to be equal or tion. Auranofin has a suppressive effect on 02- superior to GST in the adjuvant arthritic rat generation which may be biphasic and dose- model which is used in screening for antiarthritic dependent.77m79GST had minimal suppressive compounds.“,65,66 effects in these studies. Lysosomal enzyme activity is considered to Injammatory Cell Function play a key role in the inflammatory cascade of It has been postulated that some of the effects RA.80 Evaluation of lysosomal enzyme release of auranofin are mediated through alteration of (LER) by @-glucuronidase and lysozyme mark- the cellular membrane which would ultimately ers in rat leukocytes showed a dose-related inhi- affect important intracellular functions. Permu- bition with auranofin.76 “In viva” animal studies tations in plasma membrane function were were similar.” When inhibition of LER was induced by auranofin by blocking prostaglandin evaluated in healthy volunteers and patients with E,-stimulated production of cyclic AMP.67 RA, auranofin had a more pronounced effect Auranofin, but not GST, inhibited incorporation than GST with all methodologies employed.82-84 of (3H)thymidine and (14C)amino acids into In two separate studies, it was also noted that a human lymphocytes.6s Lymphocyte transforma- 43%-68% reduction in LER was correlated with tion to concanavalin A decreased progressively in clinical improvement in rheumatoid patients 29 patients given auranofin for six months.69 treated with auranofin.78184 These effects were thought to be due to interfer- Although these initial reports with auranofin ence with lymphocyte membrane transport activ- are encouraging, alterations of “in vitro” tests of ity since no effect was observed on protein syn- cellular function cannot be considered indicative thesizing mechanisms at the intracellular level. of clinical response. 260 BLODGElT, HEUER, AND PIETRUSKO

Humoral Immunity PHA and no inhibition of Epstein-Barr virus- Humoral immunity can be affected by aurano- induced lymphocyte stimulation. fin as evidenced by its inhibitory effect on anti- Variable effects have been observed with au- body to human IgE-induced release of histamine ranofin on hypersensitivity skin tests. A sup- and SRS-A from fragmented primate lung and pressed skin test response to dinitrochloroben- suppression of “7s” hemagglutinating antibody zene (DNCB) was observed in 11 of 14 patients response to sheep red blood cells.“*85~*6Auranofin receiving auranofin versus a normal response in is also capable of reducing levels of the antibodies 22 of 24 patients receiving GST.95 Normal involved in antibody-dependent cellular cytotox- responses were observed with both gold com- icity (ADCC) and antibody-dependent comple- pounds when patients were skin tested with puri- ment lysis (ADCL).86*87GST had no effect on fied protein derivative (PPD), trichophyton, and ADCC but immune sera from GST-treated rats mumps. In another study, patients treated for six enhanced ADCL in these studies. Pokeweed months with auranofin had a 33% increased skin mitogen-induced generation of immunoglobulin- test response to PPD and a 119% increased secreting cells was suppressed by auranofin in response to streptokinase/streptodornase (SK/ concentrations one tenth those of GST required SD).96 to produce a comparable level of inhibition.** In Based on analysis of their data, Lorber et al. vivo assessment of immunoglobulins and rheu- stated that the therapeutic action of auranofin matoid factors in RA showed a significant reduc- appears to be cell-mediated rather than humoral tion in circulating levels by GST and a similar when compared to GST.89 but less marked effect with auranolin.89~90Simi- lar effects on circulating immunoglobulins were Platelet Aggregation observed at six months in 50 patients switched Auranofin inhibits platelet aggregation in- from GST to auranofin when compared to 49 duced by ADP, epinephrine, and co11agen.97It control patients continued on GST therapy.” appears to inhibit both the platelet release reac- tion and platelet aggregation. Cell-Mediated Immunity RA has been described as a disease of “al- Plasma Copper and Zinc Levels tered” T lymphocyte/macrophage immunoregu- A significant decrease in serum copper levels lation9’ “In vitro” and “in vivo” studies indicate was present in a study of five patients who that auranofin can stimulate or suppress cellular responded to auranofin.98 Ceruloplasmin concen- immunity. Research is currently being con- trations were unaffected and a significant inverse ducted to determine its specific effect on T cell relationship was also noted between serum cop- function.93 Both auranofin and GST enhanced per levels and plasma zinc concentrations. the delayed hypersensitivity response to oxazo- Patients with RA who showed a pretreatment lone in mice; however, only auranofin stimulated plasma copper to ceruloplasmin ratio of greater this response in immunosuppressed animals.94 than seven were more likely to respond to chryso- The response of sensitized mice to sheep RBCs therapy than patients with a value of less than was equally stimulated by auranofin or GST. seven.99 In vitro evaluation of cell-mediated immunity ANIMAL PATHOLOGY/TOXICOLOGY with Epstein-Barr virus and phytohemagglutinin (PHA) stimulation of (3H)thymidine uptake by Acute and Subacute Toxicity lymphocytes was conducted in patients with RA The 50% lethal dose for oral auranofin is 310 on auranofin or GST.‘7*89Auranofin-treated sub- mg/kg in mice and 265 mg/kg in rats.lDOAdmin- jects recorded prompt and sharp decreases in istration of auranofin in doses up to 360 times the PHA-induced lymphoproliferative response. A human adult dose in rats for three months high degree of suppression of (3H)thymidine resulted in dose-related salivation, tenseness and incorporation with Epstein-Barr virus was also struggling during dosing, and soft stools.“’ Food observed. In contrast, patients given GST consumption was not affected but the main toxic recorded a slower onset and less suppression of effect after three months was decreased body the lymphoproliferative mitogen response with weight. In dogs receiving up to 180 times the 261 human adult dose, the principal toxic sign was the first clinical trial, and found improvement in loss of body weight. Dose-related emesis, diar- objective and subjective clinical signs as well as rhea, weight loss, and decreased food consump- resolution of biochemical and immunologic tion occurred secondary to gastrointestinal irrita- parameters.23 Similar results were observed by tion. Anemia also was observed. others. 2’~25~‘07~‘08Clinical benefits included in- creased grip strength and a reduction in the Chronic Toxicity number of tender and swollen joints, joint size, Dogs receiving six to 60 times the human adult and duration of morning stiffness. Clinical dose of auranofin for 12 months developed eme- improvement was paralleled by resolution of sis, diarrhea, a subclinical hemolytic anemia, abnormal immunoglobulin levels and rheuma- hypoproteinemia, and hyperplasia of the thyroid toid factor titers. The majority of adverse effects gland.“* In rats receiving up to 230 times the involved the gastrointestinal tract and were gen- human adult dose for one year, auranofin-related erally mild and self-limited. Data derived from lesions included renal tubular cell karyomegaly approximately 100 patients showed that aurano- and cytomegaly, renal cortical adenomas, gastric fin was absorbed orally, exhibited a therapeutic lesions, and ileocecocolic ulcers.“’ Renal tubular effect, and was well-tolerated. cell karyomegaly and cortical adenomas were After initial observations that showed aurano- also found in rats receiving GST over a similar fin to be relatively safe and well tolerated, dosage one-year period.‘0’v’03This heavy metal nephrop- range evaluations were carried out in open athy is reported to be rodent-specific.6s,‘04 trials. 2’~40~55~‘oq*“oThe initial dose of auranofin was 1 or 3 mg twice a day for one month. The Teratology dose was generally decreased after this period of Auranofin induced fetal edema in the rat and time, and the investigator was able to adjust the chiefly abdominal malformations, that is, gastro- dose based on clinical judgment after three or six chisis and umbilical hernia, in rabbits in repro- months. A general migration in dose toward 6 mg ductive studies.‘05.‘” It had a negative effect on per day followed. Although the variability in litter size, fetal weight, and resorption in rabbits dosing and open nature of the study precluded at doses 20 to 80 times the average adult human statistical analysis, it was the subjective opinion dose. These effects were not observed in rats of the investigators that auranofin was of benefit similarly tested. to most patients and it possessed an adequate safety profile. Two patients were withdrawn for CLINICAL TRIALS side effects and three patients were dropped due Over 3,000 patients with RA have received to lack of efficacy of the 87 patients treated with auranofin in the world-wide clinical trials, with auranofin during these trials. some patients on therapy for over four years. Weisman et al. found that a clinical response Auranofin has been compared with parenteral occurred in 66%-75% of the patients followed for gold salts, penicillamine, levamisole, and hy- periods up to one year in a follow-up report of droxychloroquine. Auranofin was added to a 104 patients included in seven of these original regimen of salicylates and/or a nonsteroidal studies.“’ The number of patients dropped from antiinflammatory drug (NSAID) in the majority the studies due to toxicity averaged 8%. Radio- of studies. logic evidence for inhibition of disease pro- gression was observed in three of 15 patients on Open Studies auranofin for more than four years. According to Initial open trials were designed to evaluate the investigators, auranofin’s therapeutic effect whether the effects of auranofin in laboratory was comparable to that of injectable gold for experimentation could be extended to patients most patients but without the serious toxic com- with RA. Most of these studies lasted from three plications. to six months and were limited to small groups. Preliminary reports of world-wide open stud- Laboratory parameters of disease activity were ies evaluating auranofin’s effectiveness show a carefully scrutinized. Finkelstein et al. treated 50%-75% clinical improvement rate in 276 eight patients with auranofin for three months in patients treated for up to 12 months.“2-‘20 The 262 BLODGETT. HEUER, AND PIETRUSKO dose of auranofin ranged from 4 to 8 mg daily. of auranofin in 273 patients.‘23,‘24More positive Bandilla et al. reported their experience in measures of improvement were noted at three patients given auranofin for at least one year.59 months with the 6 mg dose. However by the Seventy percent of the 91 patients improved six-month evaluation, global efficacy ratings for clinically. Subjective parameters such as morn- both the 2 and 6 mg dosage regimens were ing stiffness and overall pain showed improve- equivalent. Although the incidence of diarrhea ment as early as the twelfth week. Articular and was slightly higher for the 6 mg dose (34% vs. activity indices and erythrocyte sedimentation 22%) dropout rates due to complications were rate (ESR) showed significant changes only after similar. Thus, a quicker response seemed appar- nine months. Patients who responded well in the ent with the 6 mg dose at the expense of slightly first year of therapy continued to show improve- more frequent, but not more severe adverse reac- ment over the following years.“’ Ten patients tions. were withdrawn for lack of efficacy and 17 Weiss conducted a follow-up evaluation of patients were discontinued due to untoward patients who were enrolled in the above dosage effects during the first year of the study. Diar- range studies, some for up to 24 months.‘*’ A rhea caused discontinuation in 7%, mucocuta- dose of 6 mg per day seemed to be the most neous reactions in 3%, and leukopenia in 1%. desirable regimen. Patients receiving 6 mg daily Eight of 10 patients who received auranofin 3 had a significant decrease in morning stiffness, mg twice a day completed a two year open fatigue, and pain as well as a reduction in ESR, study? A satisfactory therapeutic response was IgA, IgM, IgG, and latex agglutination titer. Of seen in 50% of patients at six months and 75% at the 418 patients treated, 11% were withdrawn 12 and 24 months. due to lack of efficacy and 9.8% had adverse reactions requiring drug withdrawal. Diarrhea Double-Blind Controlled Studies occurred in 35% and in combination with other Two controlled, double-blind studies were con- symptoms in 53%. The incidence of dermatitis ducted to determine the ideal daily dose of was 35% and mucous membrane lesions devel- auranofin. Calin et al. reported in a multicenter oped in 10.3%. Other side-effects included pro- study that 137 patients with RA were randomly teinuria (three patients), thrombocytopenia assigned to receive either 1 or 9 mg of auranofin (three patients), abnormal liver function tests daily.*’ The code could be broken at three (two patients), and fever (one patient). months if therapeutic benefit seemed inade- Katz et al. reported on a placebo-controlled, quate. Those on low dose were entitled to have double-blind study, involving 289 patients at 18 the dosage increased to 3 mg and then to 6 or 9 centers throughout the United States.‘26 This mg. Individuals who could not tolerate the study was designed to compare the efficacy of dosage due to side-effects had the dosage auranofin 3 mg twice a day to placebo when decreased, still blinded, to 33% of the original added to a regimen of aspirin or a single NSAID. dose. Significantly more patients on 1 mg/day, It was divided into two 26-week segments; the 57% (32 of 56) at three months, dropped out due first segment being double blind and the second to lack of efficacy than those receiving 9 mg/day, portion open label with a provision to change the 33% (20 of 60). A reduction in dosage was dose. Data on 84 auranofin and 60 placebo group necessary in two patients on the 1-mg dose versus patients were analyzed for efficacy at three and 13 patients receiving the higher 9-mg dose. six months. When compared to placebo, there Diarrhea was the most frequent adverse effect was a statistically significant improvement in the and appeared to be dose-dependent. The relative number of tender and swollen joints and grip lack of efficacy of the I-mg dose and the higher strength. There were no statistically significant prevalence of diarrhea associated with 9 mg/day differences between auranofin and placebo when indicated that a dosage between these two morning stiffness or time to onset of fatigue were extremes would be more suitable for the majority evaluated. After six months, 50 (65%) of 77 of patients. patients on auranofin compared to 25 (43%) of A similarly designed study was carried out by 58 patients on placebo showed marked or moder- Bernhard et al. comparing 2 and 6 mg daily doses ate improvement. AURANOFIN IN RA 263

Significant decreases in ESR, IgM, and IgA patients), nitritoid reaction (three patients), and levels were found. Mean IgG levels were signifi- gold pneumonitis (one patient) were observed cantly decreased at three months but not at six only in the GST group. Other GST-related prob- months. Dropouts due to insufficient therapeutic lems that resulted in discontinuation of therapy effect represented 30% of all patients on placebo included skin rash (eight patients), stomatitis and only 5% on auranofin. Seven auranofin (four patients), leukopenia (one patient), and patients and one placebo patient were removed diarrhea (one patient). Withdrawals in au- from the study due to adverse reactions. Drop- ranofin treatment included one patient each for outs associated with auranofin were due to diar- rash, diarrhea, stomatitis, eosinophilia, and leu- rhea (two patients), skin rash (two patients), kopenia. proteinuria (one patient), thrombocytopenia Sixty-three of 90 initially randomized patients (one patient), and dysgeusia (one patient). The have been followed for at least six months by placebo patient was withdrawn due to protein- Lewis et al. in a placebo-controlled comparative uria. This study indicated that auranofin pro- study of auranofin and GST.‘33,‘34 Although vides a significant additional therapeutic benefit improvement was seen slightly earlier in the GST when added to a regimen of aspirin or NSAID. group, reductions in ESR and C-reactive protein were similar for both active treatment groups at Comparative Clinical Trials six months. Auranofin and GST both provided Several large double-blind studies have been favorable clinical and laboratory improvement. conducted to compare the efficacy and safety of Side effects requiring withdrawal prior to six auranofin with GST. Schattenkirchner et al. months occurred in three patients receiving au- found a marked and similar improvement in the ranofin (leukopenia, diarrhea, and hematuria) clinical and laboratory parameters of RA for and in five patients on GST (rash in three both auranofin and GST-treated groups in a patients, nitritoid reaction, and proteinuria). double-blind multicenter trial involving 121 Eleven placebo patients dropped out due to lack patients.‘27-‘30 Eighty-nine patients had been on of benefit. therapy longer than six months and 68 patients A total of 175 patients have been enrolled for longer than one year. The number of adverse in several smaller controlled comparative effects was similar in both treatment groups; trials.‘35-‘3* Preliminary evidence suggests that however, withdrawals were more frequent with the efficacy of auranofin approaches that of GST. Gastrointestinal intolerance was more fre- parenteral gold salts among the patients evalu- quent with auranofin and mucocutaneous reac- ated at six months to one year. Patient withdraw- tions were twice as common with GST. als due to adverse on-therapy conditions were A multicenter, placebo-controlled compara- generally less frequent with auranofin. tive study has been completed by the Cooperative Many open trials comparing auranofin with Systematic Studies of Rheumatic Diseases group injectable gold have been conducted or are cur- in the United States.50”3’*‘32Of 209 patients rently in progress. Menard et al. examined the initially enrolled in the study, 161 patients com- effects of auranofin and GST in 112 patients in a pleted at least 20 weeks of therapy with aurano- prospective, open study.‘39.‘40 Ninety-two pa- fin 3 mg twice a day, weekly GST injections, or tients completed three months and 65 patients placebo. Both auranofin and GST were effective continued therapy for six months. No significant and superior to placebo in improvement of pain- differences were found between the two gold ful and/or swollen joints, physician assessment compounds in terms of objective and subjective of disease activity, and decrease in ESR. How- indices of disease activity. In both groups, 50% ever, patients on GST showed a more rapid had improved after three months and 70% recovery from anemia and a reduction in throm- responded to therapy after six months. Of the 57 bocytosis when compared to auranofin-treated patients admitted into the auranofin group, seven subjects. Withdrawals for adverse effects with patients were withdrawn for lack of effect and GST were four to five times more frequent. four patients for development of side effects, Thrombocytopenia (two patients), proteinuria mainly gastrointestinal. Two patients were with- (two patients), elevated liver enzymes (three drawn for lack of effectiveness and eight patients 264 BLODGElT, HEUER, AND PIETRUSKO developed side effects that required discontinua- study involving 36 patients.“’ Clinical measure- tion of the 55 patients treated with GST. ments at six months showed no statistically sig- In another randomized, open study comparing nificant differences among the treatment groups. auranofin and GST in 60 patients, Smith et al. Four patients receiving auranofin were with- reported that after two years of therapy, 56% of drawn due to lack of efficacy and seven patients patients receiving auranofin were in remission on levamisole were removed for the same reason. versus 82% of those on GST.‘4’*‘42In a review of Three penicillamine patients were dropped due the demographic data, however, auranofin to nephrotic syndrome, severe proteinuria, and patients as a group had more active disease at the lack of effect. start of the study and there was more severe structural damage according to radiographic SAFETY analysis. None of the patients receiving aurano- Gastrointestinal and mucocutaneous reactions fin had to be withdrawn from the study com- were the major adverse effects reported in more pared with eight patients in the GST group. than 3,000 patients who received auranofin.‘* Thirty-eight patients were randomly allocated Most side-effects were mild, of short duration, to treatment with either auranofin or GST in an and usually resolved with continuation of ther- open comparison conducted by Prouse et a1.‘43,‘44 apy or a reduction in dose.‘* Although proteinu- Noticeable response commenced within six to 12 ria occurred in most studies, it was usually mild weeks as evidenced by a greater than 25% and transient with therapy being discontinued in increase in grip strength and more than a 25% 1.6% of the patients.‘* Hematologic changes reduction in joint count, morning stiffness, and necessitated withdrawal in less than 1% and pain score. Auranofin and GST appeared equally included thrombocytopenia (0.5%), anemia effective at 12 and 24 months and no major (0.l%), leukopenia (O.l%), and eosinophilia treatment problems occurred in either group. (0.1%).‘2,2’ Elevation in liver enzymes resulted in Equivalent therapeutic effects were observed discontinuation of auranofin in 0.4%. No abnor- with auranofin and parenteral gold compounds mal trends were observed in other laboratory in other open comparable trials.‘45-‘47Side effects parameters. Due to study design and anticipated were notably milder and less common in those general clinical practice, most patients were receiving auranofin. receiving concurrent salicylate or NSAID ther- Early results of an open study comparing apy and some were also on corticosteroids. auranofin with GST and penicillamine in 42 Direct comparative studies with GST show patients suggest that auranofin is well-toler- that auranofin causes fewer and less severe ate&148,149 None of the auranofin patients were adverse reactions (Fig. 3). '28.'32,'38.140.14','43,'48The withdrawn due to adverse effects at nine months, severity of side effects occurring during therapy whereas five patients on GST and one patient on can probably be ascertained best by the resultant penicillamine were discontinued. withdrawal rate. Discontinuing auranofin due to Significant improvement in disease activity adverse effects averaged 11% in 3,082 patients assessed by the usual clinical and laboratory (Fig. 4); some of whom have entered their fifth parameters was observed for both auranofin and year of therapy.‘* Withdrawal rates for paren- penicillamine in a single-blind study of 40 teral gold salts have ranged from approximately patients.96 There were no significant differences 15%-30% during the first six months of thera- between the two drugs for any of the parameters 8,9.‘52When injectable gold is continued for monitored. One auranofin-treated patient was PY. five years or longer, Lockie et al. have reported a dropped due to diarrhea and another for erosive dropout rate of 59% due to major toxicity.‘53 gastritis. Five penicillamine patients were Luukkainen also observed a dropout rate of 49% removed-four for dermatitis and one for pro- for toxic effects in 293 patients treated with teinuria (3.6 g/24 hr). Franchimont et al. parenteral gold for up to six years.ls4 reported that auranofin was as effective as peni- cillamine and better tolerated in a similar study of 46 patients.15’ Gastrointestinal Huskisson and Scott compared auranofin, Changes in stool pattern are evident in up to penicillamine, and levamisole in an open parallel 40% of patients with diarrhea being the most AURANOFIN IN RA 265

most instances, to a reduction in dosage.28~‘23The comparative trials with GST indicated that gas- trointestinal reactions, primarily diarrhea, occur twice as often with auranofin. Gastrointestinal tract complaints other than diarrhea occurred in 17% of all study patients resulting in discontinuation of auranofin in 0.9%.” Katz et al. reported that upper gastroin- testinal symptoms such as nausea, vomiting, and bloating were similar to placebo.“‘j

Mucocutaneous Reactions Approximately 30% of patients on auranofin developed a reaction related to the skin which included rash, pruritus, and rarely alopecia.*’ Fig. 3. Side effects of auranofin and gold sodium thio- Most rashes were mild in nature and discontin- malate (GSTI including 243 patients treated with auranofin and 244 patients administered GST. (Data compiled from uation of therapy was necessary in only 4%. references 129,133,139,141,142,144, and 149). Side-effects involving the mouth (stomatitis) or eye (primarily conjunctivitis) were both reported in approximately 10% and necessitated with- frequently encountered on-therapy condition.12 drawal of therapy in 1% and 0.3%, respectively. The reported effects of auranofin ranged from The incidence, severity, and need to discon- increased frequency and loose stools to frank tinue therapy resulting from mucocutaneous diarrhea. Over 50% of all episodes of diarrhea reactions were less with auranofin in comparison occurred during the first three months of therapy to GST. 50.128.140,141 and slightly less than 3% of patients have been Six cases of herpes zoster developed during withdrawn from therapy due to this problem. auranofin therapy in clinical trials in the United In the blinded dosage range studies, it was States.2’ Although patients with herpes zoster do apparent that diarrhea was more prevalent at the not have an increased prevalence of occult can- higher daily doses of auranofin and responded, in cers or increased risk of developing subsequent carcinomas as originally believed, nonetheless these cases have been observed closely because of the reported immunoregulatory activity of aura- nofin.’ All episodes cleared spontaneously despite continued therapy in five out of six patients. The incidence of herpes zoster in aura- nofin-treated patients (0.8%) was slightly higher than in patients with RA not receiving gold therapy (0.4%) but is less frequent than in patients given parenterai gold compounds (3~1%).21.‘56,157 Vasomotor (nitritoid) reactions have not been reported with auranofin.

Renal As with parenteral gold preparations and peni- cillamine, proteinuria and rarely glomeruloneph- Fig. 4. Adverse reactions resulting in patient with- ritis have been observed during auranofin thera- drawal from the study. Represents the overall clinical experience with auranofin in 3,082 patients; some who are PY.‘58*‘59 Proteinuria was generally not a major now entering their fifth year of therapy. Injectable gold salt problem. It occurred at various times during (IGSj-treated patients (N = 466) were enrolled in the comparative trials of auranofin. (Adapted from Heuer and treatment and resulted in drug discontinuation in Morris.“) 1.6%.‘* 266 BLODGETT, HEUER, AND PIETRUSKO

Development of proteinuria can also occur mal. There were no prodromal symptoms or with NSAID therapy and as a consequence of practical laboratory tests which could predict an RA. ‘60~‘6’The incidence of proteinuria was impending drop in platelet count. This reaction higher in the placebo group in the study by Katz did not appear to be related to total dose or et a1.‘26 duration of therapy. The incidence of auranofin The incidence of proteinuria in the published associated thrombocytopenia (0.5%) appears to comparative trials was 2.2% (eight of 364) for be less than that associated with injectable gold auranofin and 4.6% (13 of 28 1) with parenteral salts (l%-3%) or penicillamine (8%).‘67-‘69 gold. 50~‘28~‘40-‘49~‘62The dropout rate for protein- uria was four times as high with injectable Miscellaneous chrysotherapy (2.1% vs. 0.5%). Deposition of minute particles resembling gold Other abnormalities in renal function such as within the cornea have been identified during elevation in blood urea nitrogen, serum creati- ophthalmologic examination in two patients.‘* nine, and uric acid have also been reported and This phenomenon was not associated with ocular were associated with 0.1% of withdrawals.2’ symptoms and required no modification in thera- py. Up to 40% of patients who have received a Hepatic cumulative dose of parenteral gold exceeding Mild and transient abnormalities in serum 1,500 mg developed cornea1 chrysiasis.“’ transaminases and alkaline phosphatase have Auranofin does not appear to have significant been reported during therapy with auranofin. adverse effects upon the central nervous system Three (0.4%) of 823 patients were removed from (CNS).‘2*‘26 Only 2% noted symptoms possibly clinical trials due to elevations in liver enzymes.*’ related to the CNS among 418 patients treated This low incidence is noteworthy since almost all with auranofin for up to 24 months.‘2s Nine patients were receiving aspirin or NSAID which reports were single episodes of headache or dizzi- have known hepatotoxic potentia1.‘63*‘64Although ness and no patients were excluded from further intrahepatic cholestasis has been previously study due to these effects. described with GST, it has not been reported with auranofin.16’ RADIOGRAPHIC CHANGES The disease-modifying effect of auranofin was Hematologic assessed in 143 patients by evaluating the rate of A mean reduction in hemoglobin of 0.5 g/d1 progression of erosive changes over 12 and 24 which gradually recovered to pretreatment levels months.“‘~“* Pre- and posttherapy hand roentge- was noted in the first three months of therapy nograms were independently graded by two read- with auranofin.‘* Mild anemia occurred in a few ers blinded for sequence and source of film. Two instances which resulted in discontinuation of different methods of analysis were employed. auranofin in four patients. When compared to films from a prior placebo- Intermittent elevations and depressions of the treated group of patients, auranofin slowed the WBC count were observed in patients with RA progression of erosive disease. on auranofin. However, only 11 patients (0.4%) Three of 15 patients treated with auranofin were removed because of leukopenia.‘* The after four years were judged as having sustained WBC returned to normal levels after discontin- radiographic improvement when evaluated by a uation. Several cases from the European experi- radiologist blinded to patient identity and film ence had evidence of peripheral destruction of sequence. “’ The effects of auranofin on retard- neutrophils. Eosinophilia has resulted in the dis- ing joint-space erosion were considered similar to continuation of therapy in one patient. those that have been reported to occur with Six cases of thrombocytopenia (platelet conventional parenteral gold therapy. A radio- count <100,000/mm3) possibly related to aura- graphic comparison of 83 patients receiving nofin have been evaluated.‘66 Once thrombocyto- auranofin and 74 patients on parenteral gold for penia was detected, discontinuing auranofin 12 months showed that both medications could resulted in a return to a normal platelet count retard the progression of joint erosion and mean within one to eight weeks. Morbidity was mini- joint grade.‘73 Of the patients receiving intra- AURANOFIN IN RA 267 muscular gold injections, 72% showed no pro- group, there was no evidence of clinical deterio- gression in joint erosion compared to 58% of the ration in the auranofin switchover subjects dur- auranofin-treated patients. ing the six month study. Laboratory parameters of underlying disease activity were similar in DRUG INTERACTIONS both treatment groups. Two of the patients switched to auranofin and three of the patients Information concerning potential drug inter- maintained on GST failed to complete the study actions with auranofin is limited. Salicylates, because their disease could not be controlled. No NSAIDs, and corticosteroids have been adminis- new or unusual patterns of toxicity developed tered concurrently without apparent hazard in during the overlap period when GST and aurano- the clinical studies involving auranofin.” Thus fin were administerd simultaneously. In a far, there do not appear to be any therapeutic smaller switchover study involving 38 patients, problems caused by coadministration of aurano- clinical indices of efficacy were comparable for fin with a variety of other agents. auranofin and GST at the completion of the tria1.‘62 However, in terms of improvement in DOSAGE laboratory parameters of disease activity, there The dose of auranofin most commonly was a more marked trend in favor of GST. employed during the clinical trials was 6 mg given once daily or in two divided doses. Side SUMMARY effects including dose-related alterations in Auranofin is a chemically unique gold coordi- bowel habit did not appear to differ in patients nation complex with demonstrated antiarthritic receiving either dosage regimen.12 Since patient properties on oral administration. Its pharmaco- compliance could be enhanced with a once a day kinetic and immunologic profiles are distinct dosage schedule during chronic auranofin thera- from injectable gold compounds. py, a major study is now underway to compare When auranofin is added to a regimen of the safety and efficacy of 6 mg administered salicylates and/or a nonsteroidal antiinflamma- once daily in the morning or evening versus 3 mg tory drug for the treatment of RA, significant twice a day.12’ To date, 449 patients have been additional therapeutic benefit is observed. Pub- entered and the preliminary data suggest that the lished studies indicate that auranofin given 6 mg number of untoward events and withdrawal rates per day approaches the efficacy of parenteral are similar in both groups. All parameters of gold salts in the treatment of rheumatoid disease. efficacy improved and no differences in response Noticeable improvement in clinical and labora- could be detected in either group. tory parameters of disease activity has been Intermittent therapy with auranofin (3 mg observed by the third month of auranofin thera- once daily every other week) proved to be less py. Further benefit occurs in some patients dur- effective than continuous therapy with 6 mg ing the remainder of the first year of treatment. daily.‘74 In the more than 3,000 patients treated with It may be anticipated that patients currently auranofin, the most frequently reported side receiving injectable gold salts would be converted effects were gastrointestinal (mainly diarrhea) to auranofin because of its relative safety and and mucocutaneous. Most side effects were mild ease of oral administration.” In a placebo- in nature and the withdrawal rate due to all controlled, double-blind study, 99 patients were adverse reactions averaged 11%. randomly assigned to receive either continued Auranofin differs from injectable gold by pro- GST therapy or auranofin therapy for six ducing more gastrointestinal but fewer mucocu- months.” All of the patients were receiving GST taneous reactions. The severity of these reactions prior to study entry and were clinically con- is less with auranofin and causes fewer with- trolled. When compared to the GST control drawals from therapy.

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