BACKGROUND: Zoledronic acid has demonstrated efficacy and safety in the treatment of bone lesions in patients with multiple myeloma. However, bisphosphonates are known to have dose-dependent and infusion rate-dependent effects on renal function and patients with multiple myeloma may have disease-associated compromise of renal function. The pharmacokinetics (PK), pharmacodynamics (PD), and safety of monthly intravenous (IV) infusions of zoledronic acid (4, 8, and 12 mg) were investigated in a subset of patients with multiple myeloma as part of an open-label, phase I, multiple-dose study. Doses higher than the approved 4-mg dose were infused over 1 or 2 hours based on an infusion-rate model that predicted a Cmax similar to that of the approved regimen (4 mg via 15-minute IV infusion). Moreover, levels of tumor markers were measured to assess potential clinical antitumor activity at various dose regimens.
METHODS: Patients received a total of 6 infusions of zoledronic acid in 28-day cycles: 4 mg via 15-minute infusion on day 1; 8 mg via 60-minute infusion on days 29 and 57; 12 mg via 120-minute infusion on days 85 and 113; and 4 mg via 15-minute infusion on day 141.
RESULTS: Ten patients with multiple myeloma were enrolled, and 7 completed all 6 infusions. Median age was 58 years, ECOG performance status was ≤ 1 in 9 patients and 2 in 1 patient; 80% had received prior antineoplastic therapy, and 100% had received prior radiation and/or surgery. Three patients discontinued because of abnormal laboratory values (n = 2) or withdrawal of consent (n = 1). The most common AEs were fatigue (60%), myalgia (50%), arthralgia (40%), and nausea (40%). Increased serum creatinine > 0.3 mg/dL over baseline prompted a dose delay/reduction in 1 patient and discontinuation of treatment in 2 patients. In multiple myeloma patients, mean Cmax (± SD) was 329 (± 89) ng/mL after the first 4-mg dose infused over 15 minutes (1st infusion), 407 (± 105) ng/mL after the 2nd 8-mg dose infused over 60 minutes (3rd infusion), and 385 (± 114) ng/mL after the 2nd 12-mg dose infused over 120 minutes (5th infusion). Increasing doses produced proportional increases in drug exposure (AUC). Decreases from baseline were observed in serum markers of bone resorption; however, there were no consistent or meaningful changes in tumor marker levels (eg, serum IL-6).
CONCLUSIONS: This study indicates that by prolonging infusion times to 1 hour and 2 hours using 8-mg and 12-mg doses of zoledronic acid, respectively, Cmax can be maintained and is similar to that obtained with the approved 4-mg dose infused over 15 minutes.