Phase 1 Assessment of an Orally Bioavailable Formulation of Gallium Nitrate (G4544).

Background: High intravenous doses of gallium nitrate (GN) (200–300 mg/m2/day for 5–7 days) are extremely effective for treatment of patients (pts) with cancer-related hypercalcemia, and preliminary studies have shown consistent anticancer activity in pts with relapsed non-Hodgkin’s lymphoma (NHL). In preclinical studies, low concentrations of GN act as a potent inhibitor of osteoclast-mediated bone resorption, and the agent may also have anabolic effects on bone formation. Clinical studies have shown that low doses of GN (0.25–0.5 mg/kg/day x 14 days) administered by subcutaneous (SC) injection significantly reduced metabolic markers of disordered bone turnover in advanced Paget’s disease. Moreover, a multi-year longitudinal study in pts with advanced multiple myeloma showed that similarly low doses of GN administered by intermittent SC injection significantly reduced bone loss in pts receiving M-2 chemotherapy, and this therapy may have been associated with increased survival (Niesvizky R, Semin Oncol30 (Suppl. 5): 20–4, 2003). GN has low oral bioavailability, and in order to improve dosing convenience over extended periods, we have investigated the oral absorption of numerous gallium-containing compounds. We have successfully developed a novel formulation of GN (G4544) that has acceptable oral bioavailability, and this formulation has now advanced into initial clinical studies. Methods: GN was formulated with a proprietary functional excipient (Emisphere Technologies, Inc.), and compressed into tablets containing 30 mg of elemental gallium by weight (G4544). Oral availability of the formulation was tested in comparison with a control formulation without the functional excipient in dogs. G4544 was then examined in a dose-ranging study to assess safety and pharmacokinetics (PK) following administration of single oral doses to healthy male volunteers. Individual patient cohorts (6 subjects per level) received doses starting at 30 mg gallium and increasing to 60, 90, 120, and 150 mg. Plasma samples were assayed periodically to evaluate PK. Results: Non-clinical studies showed that tablets containing the functional excipient significantly increased gallium absorption compared to controls lacking excipient. The increase in plasma gallium exposure was up to 2.2-fold in AUC and 2.8-fold in Cmax. After a single dose of G4544, the observed mean Cmax and mean AUC0-inf for G4544 was 1.5 ug/mL and 33.0 hr*mg/mL, respectively, compared to 0.5 ug/mL and 14.8 hr*mg/mL for the control formulation. PK assays of clinical samples are pending and will be presented. Conclusions: Low doses of GN have highly potent anti-resorptive effects on bone, and potentially direct activity against myeloma and NHL cells. G4544 markedly increases the oral absorption of GN and may extended oral dosing for treatment of diseases associated with accelerated bone resorption. Follow-up clinical trials are planned to establish the bioequivalence of G4544 to the currently available parenteral formulation for acute treatment of cancer-related hypercalcemia.