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The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralization or mechanical properties of bone.
In addition to being a very potent inhibitor of bone resorption, zoledronic acid also possesses several antitumor properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies: In Vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment making it less conducive to tumor cell growth, antiangiogenic activity, anti-pain activity.
In Vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumor cells, synergistic cytostatic effect with other anticancer drugs, anti-adhesion/invasion activity.
Clinical Studies: Clinical Trial Results in the Treatment of Osteolytic, Osteoblastic and Mixed Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma, in Conjunction with Standard Antineoplastic Therapy and Reduction of Bone Damage in Patients with Advanced Malignancies Involving Bone: Zometa was compared to placebo for the prevention of skeletal-related events (SREs) in adult prostate cancer patients with 214 men receiving Zometa 4 mg versus 208 receiving placebo. After the initial 15 months of treatment, 186 patients continued for up to an additional 9 months, giving a total duration of double-blind therapy up to 24 months. Zometa 4 mg demonstrated a significant advantage over placebo for the proportion of patients experiencing at least 1 SRE (38% for Zometa 4 mg vs 49% for placebo, p=0.028), delayed the median time to 1st SRE (488 days for Zometa 4 mg vs 321 days for placebo, p=0.009), and reduced the annual incidence of event per patient, skeletal morbidity rate (0.77 for Zometa 4 mg vs 1.47 for placebo, p=0.005). Multiple event analysis showed 36% risk reduction in developing SREs in the Zometa group compared with placebo (p=0.002). Pain was measured at baseline and periodically throughout the trial. Patients receiving Zometa reported less increase in pain than those receiving placebo, and the differences reached significance at months 3, 9, 21 and 24. Fewer Zometa patients suffered pathological fractures. The treatment effects were less pronounced in patients with blastic lesions. Efficacy results are provided in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageIn a 2nd study, Zometa reduced the number of SREs and extended the median time to an SRE by over 2 months in the population of adult patients who had other solid tumors involving bone, which had a median survival of only 6 months [134 patients with non-small cell lung cancer (NSCLC), 123 with other solid tumors treated with Zometa vs 130 patients with NSCLC, 120 with other solid tumors treated with placebo]. After 9 months of initial treatment, 101 patients entered the 12-month extension study and 26 completed the full 21 months. Zometa 4 mg reduced the proportion of patients with SREs (39% for Zometa 4 mg vs 48% for placebo, p=0.039), delayed the median time to 1st SRE (236 days for Zometa 4 mg vs 155 days for placebo, p=0.009) and reduced the annual incidence of events per patient-skeletal morbidity rate (1.74 for Zometa 4 mg vs 2.71 for placebo, p=0.012). Multiple event analysis showed 30.7% risk reduction in developing SREs in the Zometa group compared with placebo (p=0.003). The treatment effect in NSCLC patients appeared to be smaller than in patients with other solid tumors. Efficacy results are provided in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageIn a 3rd phase III randomized, double-blind trial comparing Zometa 4 mg to pamidronate 90 mg, 1122 adult patients (564 Zometa 4 mg, 558 pamidronate 90 mg) with multiple myeloma or breast cancer with at least 1 bone lesion were treated with Zometa 4 mg or pamidronate 90 mg every 3-4 weeks. Eight patients were excluded from the efficacy analysis because of good clinical practice noncompliance. Six hundred six (606) patients entered the 12-month, double-blind extension phase. Total therapy lasted up to 24 months. The results demonstrated that Zometa 4 mg showed comparable efficacy to pamidronate 90 mg in the prevention of SREs. The multiple event analyses revealed a significant risk reduction of 16% (p=0.03) in patients treated with Zometa 4 mg. Efficacy results are provided in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageIn clinical trials performed in adult patients with bone metastases or osteolytic lesions, the overall safety profile amongst all treatment groups (zoledronic acid 4 mg and pamidronate 90 mg and placebo) was similar in types and severity.
Zometa was also studied in a double-blind, randomized, placebo-controlled trial in 228 adult patients with documented bone metastases from breast cancer to evaluate the effect of Zometa on the SRE rate ratio, calculated as the total number of SRE events (excluding hypercalcemia and adjusted for prior fracture), divided by the total risk period. Patients received either Zometa 4 mg or placebo every 4 weeks for 1 year. Patients were evenly distributed between Zometa-treated and placebo groups.
The SRE rate ratio at 1 year was 0.61, indicating that treatment with Zometa reduced the rate of occurrence of SREs by 39% compared with placebo (p=0.027). The proportion of patients with at least 1 SRE (excluding hypercalcemia) was 29.8% in the Zometa-treated group versus 49.6% in the placebo group (p=0.003). Median time to onset of the first SRE was not reached in the Zometa-treated arm at the end of the study and was significantly prolonged compared to placebo (p=0.007). Zometa reduced the risk of SREs by 41% in a multiple event analysis (risk ratio=0.59, p=0.019) compared with placebo.
In the Zometa-treated group, decreases in pain scores from baseline [using the brief pain inventory (BPI)] occurred from 4 weeks onwards and at every subsequent time point during the study, while the pain score in the placebo group remained unchanged or increased from baseline (see figure). Zometa inhibited the worsening of the analgesic score more than placebo. In addition, 71.8% of Zometa-treated patients versus 63.1% of placebo patients showed improvement or no change in the ECOG performance score at the final observation.
Click on icon to see table/diagram/imageClinical Trial Results in the Treatment of Hypercalcemia of Malignancy (HCM): Clinical studies in HCM demonstrated that the effect of zoledronic acid is characterized by decreases in serum calcium and urinary calcium excretion.
To assess the effects of Zometa versus pamidronate 90 mg, the results of 2 pivotal multicentre studies in adult patients with HCM were combined in a pre-planned analysis. The results showed that Zometa 4 and 8 mg were statistically superior to pamidronate 90 mg for the proportion of complete responders at days 7 and 10. There was faster normalization of corrected serum calcium at day 4 for Zometa 8 mg and at day 7 for Zometa 4 and 8 mg. The following response rates were observed: See Table 4.
Click on icon to see table/diagram/imageMedian time to normocalcemia was 4 days. By day 10, the response rate was 87-88% for the Zometa treatment groups versus 70% for pamidronate 90 mg. Median time to relapse (re-increase of albumin-corrected serum calcium ≥2.9 mmol/L) was 30-40 days for patients treated with Zometa versus 17 days for those treated with pamidronate 90 mg. The results showed that both Zometa doses were statistically superior to pamidronate 90 mg for time to relapse. There were no statistically significant differences between the 2 Zometa doses.
In clinical trials performed in adult patients with HCM, the overall safety profile amongst all 3 treatment groups (zoledronic acid 4 and 8 mg and pamidronate 90 mg) was similar in types and severity.
Pharmacokinetics: Single and multiple 5- and 15-min infusions of zoledronic acid 2, 4, 8 and 16 mg in 64 patients with bone metastases yielded the following pharmacokinetic data.
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcemia.
After initiating the infusion of zoledronic acid, the plasma concentrations of drug rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hrs and <1% of peak after 24 hrs, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the 2nd infusion of drug on day 28.
Distribution: Zoledronic acid shows no affinity for the cellular components of blood and plasma protein binding is low (60-77%) and slightly dependent on the concentration of zoledronic acid.
Biotransformation/Metabolism: Zoledronic acid is not metabolized and is excreted unchanged via the kidney. Zoledronic acid does not inhibit human P-450 enzymes in vitro.
Elimination: Intravenously administered zoledronic acid is eliminated via a triphasic process: Rapid biphasic disappearance from the systemic circulation, with half-lives (t½) of t½α 0.24 and t½β 1.87 hrs, followed by a long elimination phase with a terminal elimination t½ of t½γ 146 hrs. There was no accumulation of drug in plasma after multiple doses of Zometa given every 28 days. Over the first 24 hrs, 39±16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue, it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04±2.5 L/hr, independent of dose.
Linearity/Non-linearity: The zoledronic acid pharmacokinetics were found to be dose dependent. Increasing the infusion time from 5-15 min caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.
Special Populations: Hepatic Impairment: No pharmacokinetic data for zoledronic acid are available in patients with hepatic impairment. Zoledronic acid does not inhibit human P-450 enzymes in vitro, shows no biotransformation and in animal studies <3 % of the administered dose was recovered in the feces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.
Renal Impairment: The renal clearance of zoledronic acid was significantly positively correlated with creatinine clearance, renal clearance representing 75±33% of the CrCl, which showed a mean of 84±29 mL/min (range 22-143 mL/min) in the 64 cancer patients studied. Population analysis showed that for a patient with CrCl of 50 mL/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 72% of that of a patient showing CrCl of 84 mL/min. Only limited pharmacokinetic data are available in patients with severe renal impairment (CrCl <30 mL/min). The use of Zometa is not recommended in patients with severe renal impairment (see Precautions).
Effect of Gender, Age and Race: The 3 pharmacokinetic studies conducted in cancer patients with bone metastases reveal no effect by gender, race, age (range 38-84 years), and body weight on zoledronic acid total clearance.
Toxicology: Nonclinical Safety Data: Acute Toxicity: The highest nonlethal single IV dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats.
Subchronic and Chronic Toxicity: Zoledronic acid was well tolerated when administered SC to rats and IV to dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day SC in rats and 0.005 mg/kg/day IV in dogs for up to 52 weeks was also well tolerated.
Reproduction Toxicity: Zoledronic acid was teratogenic in the rat at SC doses ≥0.2 mg/kg. Although no teratogenicity or fetotoxicity was observed in the rabbit, maternal toxicity was found.
Mutagenicity and Carcinogenic Potential: Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
Local Tolerance: Local tolerance testing in rabbits showed that IV administration was well tolerated.
