Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases

Abstract

The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half-lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half-lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose proportional and showed little accumulation (AUC0-24 h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines. Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54 +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23, 82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%), N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24 h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

“…Both reports involved higher doses and more frequent administration of zoledronic acid compared with our study, and significantly higher than those used in the clinical treatment of cancer-induced bone disease (4 mg infusion; ref. 17). Although the dose of 100 μg/kg research grade zoledronic acid (disodium salt, 4.75 hydrate) we used equates to the 4-mg clinical dose, this was administered weekly as opposed to every 3 to 4 weeks in clinical use.…”

“…In vitro studies have clearly shown the potential for zoledronic acid to induce direct antitumor effects including inhibition of tumor cell growth, induction of apoptosis, (9)(10)(11), inhibition of adhesion and invasion (12)(13)(14), and antiangiogenic activity (15,16). However, the concentrations of bisphosphonates used in these studies range from 5 to 20 μmol/L for up to 72 hours, compared with the 2 μmol/L circulating plasma concentration detectable in breast cancer patients for 1 to 2 hours following the standard 4-mg infusion of zoledronic acid (17). Antitumor effects of bisphosphonates have also been reported in in vivo model systems that mimic tumorinduced bone disease from a variety of cancer types including breast (18,19), prostate (20), leukemia (21), and multiple myeloma (22).…”

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

“…Both IC 50 s of ZOL against parental and P-gp-overexpressing leukaemic cells are above 60 mM, whereas of those against osteosarcoma cells were much less. It could, therefore, be argued that in the cell lines that we used, the P <0.001 P <0.001 P<0.001 P >0.05 P >0.05 P >0.05 According to a previous study evaluating ZOL efficacy for the treatment of osteoporosis (Chen et al, 2002), peak serum concentrations were in the range of 1 -3 mM and maintained for only a few hours. As IC 50 s of ZOL for MOS and LM8 cells are 1.56 and 7.36 mM, respectively, it is likely that the effect of ZOL alone might be insufficient.…”

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

“…infusion of the recommended clinical dose of zoledronic acid (4 mg), the drug remains in the plasma for less than 1 hr before localizing to bone. 39 Therefore, we exposed MCF7 cells to increasing concentrations of zoledronic acid for 1 hr only, followed by washing to remove the drug and a further 72-hr incubation in fresh medium. We found that zoledronic acid still induced a concentration-dependent increase in apoptosis (maximum, 4.5% apoptosis with 100 M zoledronic acid; p ϭ 0.002 compared to control; Fig.…”