The Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Varying Degrees of Renal Function

Abstract

An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometa) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1-month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C-labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C-telopeptide and N-telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

“…47,48 This is 10-100-fold less than the levels required to inhibit cell growth or induce apoptosis in vitro. There are no data available, as yet, on the bioavailability of ZOL in bone marrow cells.…”

Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

“…It has been reported that the peak concentration of ZOL in serum, which is maintained only for a few h, is 1-3 µM (29). This observation indicates that the optimal serum concentrations of ZOL may not be readily achieved for its antitumor activity.…”

Anticancer effects of zoledronic acid against human osteosarcoma cells

“…The observed anticancer activity was exerted at ZOL concentrations (IC 50 from approximately 9-50 mM) above the respective serum levels achieved during ZOL treatment (maximally 1-2 mM). 19 However, by far higher levels of bisphosphonates than those exhibiting anticancer activity in vitro are present at local bone resorption sites (up to 1 mM). 3 Interestingly, normal osteoblastlike cells were relatively insensitive against ZOL as compared to tumor cells.…”