Gallium nitrate and citrated gallium nitrate

Most data on the biological and therapeutic activities of gallium derive from investigations using gallium nitrate in aqueous solution. The term 'gallium nitrate,' however, has not been used consistently: it has been used to describe (a) chelator-free gallium nitrate solutions, employed for most of the in vitro and some of the animal studies and (b) gallium nitrate solutions containing citrate as a chelator, employed for all of the clinical studies and some of the animal studies. Chelator-free gallium nitrate solutions contain ionic gallium (mostly as the pH-dependent hydroxide species discussed previously), whereas citrate-containing solutions at neutral pH contain gallium citrate as a coordination complex. The commercially available product for injection (GaniteTM) contains 97.8 mM of both gallium and citrate at neutral pH,61 which allows essentially all the gallium to bind to citrate, with very little gallium remaining in other forms. This solution is here referred to as 'citrated gallium nitrate' or 'CGN,' whereas gallium nitrate without citrate or other chelators is abbreviated 'GN.' Dose levels for both GN and CGN are given in terms of anhydrous gallium nitrate (Ga(NO3)3).

In vitro and non-human in vivo studies

Anti-tumor activity of GN was first reported in 1971:62 efficacy was demonstrated against Walker 256 ascites carcinosarcoma in rats (GaCl3 and Ga(SO4)3 • 18H2O had very similar effects), and >90% growth inhibition was observed for six of eight solid tumors implanted subcutaneously (sc) in rodents. Complete tumor regression occurred in several animals. Unchelated, acidic GN solutions were administered intraperitoneally (ip) daily for 10 days; LD10 (at 30 days) was 63mg/kg (mouse), 50mg/kg (rat); LD50 was 80mg/kg (mouse), 67.5mg/kg (rat); and the effective dose varied from 30 to 60mg/kg. In vitro, GN gave an ID50 of 355 mM (anhydrous basis) against Walker 256 carcinosarcoma cells.63 In vivo efficacy against implanted human medulloblastoma (Daoy cells) was observed in nude mice that received ip GN (50 mg/kg/day for 10 or 15 days): the growth rate of macroscopic tumors was reduced or reversed64 and the progression of microscopic disease delayed.65

The finding of an anti-hypercalcemic effect in humans, which results from inhibited bone resorption rather than increased urinary calcium excretion,66,67 stimulated considerable research on gallium's bone-related activity (reviews: 9,68). Gallium concentrates in skeletal tissue, particularly at sites of rapid bone mineral deposition such as active metaphyseal growth plates and healing fractures.5,6,69,70 Concentration on the endosteal and periosteal surfaces of diaphyseal bone also occurs, but to a lesser extent.70 Several studies (using bone fragments in vitro or implanted in rodents) found that gallium adsorbs to bone surfaces and then inhibits osteoclastic bone resorption;71 73 gallium-treated bone is also less soluble in acetate buffer and less readily resorbed by monocytes.74 Gallium does not enter the crystal lattice of hydroxylapatite, but rather deposits in part on bone mineral surfaces, possibly as gallium phos-phate.75 At anti-resorptive concentrations (up to at least 15 mM, and possibly >100 mM), GN does not affect osteoclast morphology or viability,67,71,73 or act as an osteoclastic metabolic inhibitor, as do bisphosphonates.76 Gallium is found to directly inhibit the osteoclast vacuolar-class ATPase proton pump.76 In young female rats, administration of ip GN resulted in bone containing more calcium, having a larger average hydroxylapatite crystallite size, and having a higher density relative to that in untreated individuals.69,74

Some in vitro data indicate that GN may stimulate bone formation. Experiments with rat osteogenic sarcoma (ROS) and normal rat osteoblast cells found that GN can decrease osteocalcin (OC) and OC mRNA levels77,78 and increase c-fos mRNA levels;79 both activities are associated with bone formation. In vivo and clinical studies have not shown clear, consistent anabolic activity, though elevated plasma alkaline phosphatase (a marker of bone formation) was observed in post-menopausal women treated with CGN.80

Gallium nitrate and other gallium salts have shown selective in vitro and in vivo immunomodulating activity. This activity appears to stem primarily from inhibition of some T-cell activation and proliferation48,80 82 and inhibition of inflammatory cytokine secretion by activated macrophages,80,83,84 without generalized cytotoxicity to lymphocytes or macrophages. Some of the selective anti-inflammatory activity may be due to pro-inflammatory T-helper type 1 (Th-1) cells being much more sensitive to inactivation by iron deprivation than anti-inflammatory, pro-antibody Th-2 cells.85 Synoviocyte matrix metalloproteinase activity (elevated in inflammatory joint diseases) was also shown to be dose-dependently inhibited by GN at concentrations of 10-100 mM.86 In animal models, GN has shown efficacy in suppressing adjuvant-induced arthritis,80 experimental encephalomyelitis,81 experimental autoimmune uveitis,87 type 1 diabetes,88 endotoxic shock,89,90 and allograft rejection.91

Clinical experience

Parenterally administered CGN has demonstrated single-agent clinical efficacy in cancer-related hypercalcemia (for which it is approved in the United States), Paget's disease of bone, and several types of cancer, including lymphoma (43% response in relapsed malignant non-Hodgkin's lymphoma),66,92 advanced refractory urothelial carcinoma (17% response),93 advanced bladder carcinoma (40% average response in two studies),94,95 advanced or recurrent epithelial ovarian carcinoma resistant to cisplatin (12% response),96 metastatic or advanced non-squamous cell cervical carcinoma (12% response),97 advanced or recurrent squamous cell carcinoma (8% response)98 and metastatic prostate cancer (2 of 23 patients had partial response, and 7 had reduction in bone pain after treatment for only 7 days).99

Early anti-cancer clinical trials employed short (generally <30min) iv bolus infusions at doses up to 1350 mg/m2;100 subsequently, only prolonged (generally >5 days) iv infusions or sc injections have been used, due to dose-limiting renal toxicity from bolus iv dosing.

For cancer-related hypercalcemia, CGN is administered as a continuous iv infusion for 5 days at 200mg/m2/day (~5mg/kg/day).101,102 Studies comparing CGN to other anti-hypercalcemic drugs found that the proportion of patients achieving normocalcemia was higher for those receiving CGN than for those receiving pamidronate,103 calcitonin101 or etidronate.104

A small study105,106 found that CGN may be particularly efficacious against multiple myeloma. Thirteen relapsed multiple myeloma patients (11 at stage III) were treated for 6 or 12 months with sc CGN at 30mg/m2/day, administered for two weeks followed by two weeks without therapy, together with the M-2 chemotherapy protocol. A 5-day iv infusion of 100mg/m2/day CGN was administered every other month. These patients were matched with 167 similar patients who received only M-2 therapy. Patients receiving CGN showed an increase in total body calcium (decreased bone resorption), stabilized measures of bone density, reduction in vertebral fractures and decreases in measures of pain versus those not receiving CGN. Significantly, mean survival in the CGN-treated group was 87+ months, with several long-term survivors (including stage III patients (at presentation) alive at 137+ and 144+ months, and a stage IIIB patient alive at 96+ months in complete remission), compared to mean survival of 48 months in the 167 patients who received M-2 chemotherapy alone, with no long-term survivors.

Markers of bone turnover were significantly reduced in drug-resistant patients with Paget's disease of bone (a disease characterized by localized, greatly accelerated bone remodeling) who received relatively low doses of CGN (iv at 100 mg/ m2/day for 5 days107 or sc at 0.25 or 0.5mg/kg/day in two non-consecutive 14-day cycles).108 No drug-related adverse events were reported other than moderate, transient reductions in hemoglobin and serum iron-binding capacity.

Pharmacokinetics

Data on the pharmacokinetics of CGN are sparse and show significant individual variability;109 112 much of the variability may be due to differences in renal function or the extent of metastatic disease (because neoplastic tissue and associated areas of inflammation may take up significant amounts of gallium). Steady-state plasma gallium levels of 1.2-1.5 mg/ml were achieved within 48 h in eight hypercalcemic patients who received 200 mg/m2 CGN as a continuous infusion for 5 days, and levels of 1.0-1.3 mg/ml were achieved in six patients who received 100mg/m2 on the same schedule (plus one patient whose plasma gallium level never exceeded 0.45 mg/ml).112 A gallium plasma level of 1 mg/ml was considered therapeutic for cancer-related hypercalcemia in this study. The non-linear dose/plasma concentration relationship was not discussed. Elimination of gallium following administration of iv CGN is considered biphasic, with an initial elimination half-life of 0.15 to 1.5 h and a terminal half-life of 6 to 196 h; more than half of the administered dose is generally excreted in the urine within 24h.109 111 In a single patient who received CGN at 0.5mg/kg (20mg/m2) sc daily for 14 days, maximal gallium plasma concentrations of 0.95 to 1.85 mg/ml occurred 1-2 h after injection; 19% of the administered gallium was renally excreted on day 1, and 28% by day 7.113

Toxicity

The major toxicity associated with iv CGN is renal, as indicated by proteinuria, increases in blood urea nitrogen (BUN) and serum creatinine, and a decrease in creatinine clearance. Rats given ip CGN at 100mg/kg develop renal tubule damage, which is caused at least in part by precipitation of gallium and calcium phosphates within the tubule lumina.114 In humans, renal toxicity is consistently observed following a 30-min infusion of >750mg/m2, though it is ameliorated by concomitant mannitol diuresis.110 At lower doses or with longer infusion times, renal toxicity is reduced: in well-hydrated patients receiving 300 400 mg/m2/day for 7 days, markers of renal tubule damage are not significantly elevated,115 and well-hydrated hypercalcemia patients receiving 200 mg/m2/day for 5 days rarely show significant impairment of creatinine clearance.101,104,112

Another dose-related toxicity observed is anemia, which is generally mild (<3 g/dl decrease in hemoglobin) and has only been clinically significant at high bolus iv doses.100,110 When CGN is administered as prolonged infusions at 200-300mg/m2, decreases in hemoglobin are usually no more than 1-2g/dl.66,105,108 The anemia, when observed, is similar to that arising from iron deficiency, with hypochromia and microcytosis; iron-binding capacity is slightly decreased, while serum iron, TF and ferritin levels are normal.116

Other adverse events occasionally observed following slow iv infusion of CGN that may be drug-related include nausea and vomiting,96 mild respiratory alkalosis,116 hypophosphatemia,116 hypocalcemia 116 and optic neuritis.117

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