Clinical studies in patients with hypercalcemia of malignancy (HCM) show that single dose infusions of Zoledronic acid for injection are associated with decrease in serum calcium and phosphorus and increase in urinary calcium and phosphorus excretion.
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: Humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation.
Mechanism of Action:
Studies suggest that the principal pharmacologic action of zoledronic acid is the inhibition of bone resorption. Several factors are thought to contribute to the antiresorptive mechanism but the exact mechanism of action is not completely understood. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Reports from studies of single or multiple (q 28 days) 5 minute or 15 minute infusions of 2, 4, 8 or 16 mg Zoledronic acid for Injection administered to patients with cancer and bone metastases showed that the post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to <1% of Cmax
24 hours post-infusion with population half lives of t½a
0.24 hours and t 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between days 2 and 28 post-infusion and a terminal elimination half-life t½g
of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h
) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low with mean AUC0-24h
ratios for cycles 2 and 3 versus 1 of 1.13±0.30 and 1.16±0.36, respectively. In vitro and ex vivo studies show a low affinity of zoledronic acid for the cellular components of human blood. In vitro, mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. Zoledronic acid has a high affinity for calcified tissues ie., bone. No information is available with regard to crossing over of Zoledronic acid across the blood brain barrier. Zoledronic acid shows as much as 56% binding to plasma proteins.
Zoledronic acid does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose can be found in the feces with the balance either recovered in the urine or taken up by bone indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14
C zoledronic acid in patients with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug may be recovered in urine, which suggests that zoledronic acid is not metabolized. No active or inactive metabolites have been reported.
Study reports suggest that in patients with cancer and bone metastases, on average (± s.d.) 39±16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7±2.0 L/h. Zoledronic acid clearance is independent of dose but dependent upon the patient's creatinine clearance. Zoledronic acid is excreted renally as intact drug. The renal clearance correlates with creatinine clearance in patients with mild-moderate renal failure. The terminal t½
is reported to be around 146 hours.
Special Population: Pediatrics:
Zoledronic acid is not indicated for use in children.
The pharmacokinetics of zoledronic acid may not be affected by age in patients with cancer and bone metastases with the age ranging from 38-84 years.
Race: Reports suggest that pharmacokinetics of zoledronic acid is not affected by race in patients with cancer and bone metastases.
Pharmacokinetic studies indicate that patients with normal renal function (creatinine clearance >80 mL/min), patients with mild renal impairment (creatinine clearance = 50-80 mL/min) show an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (creatinine clearance = 30-50 mL/min) show an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of 35 mL/min. Zoledronic acid is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) due to lack of clinical experience in this population.
Based on population pK/pD, modeling the risk of renal deterioration appears to increase with AUC and doubles at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:
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The systemic clearance of Zoledronic acid for injection in individual patients can be calculated from the population clearance of Zoledronic acid for injection, CL (L/h)=6.5 (CLcr/90) 0.4. This formulae can be used to predict the AUC of Zoledronic acid for injection in patients, where CL = Dose/AUC0-8
. The average AUC0-24h
in patients with normal renal function was 0.42 mgh/L and the calculated AUC0-8
for a patient with creatinine clearance of 75 mL/min was 0.66 mgh/L following a 4 mg dose of Zoledronic acid for injection. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed.
No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Toxicology: Non-Clinical Toxicology: Carcinogenesis:
Standard lifetime carcinogenicity bioassays were conducted in mice and rats by administering oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. Reports suggest an increased incidence of Harderian gland adenomas in male and female mice in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg based on a comparison of relative body surface areas). No increased incidence of tumors was observed in rats (at doses ≤0.2 times the human intravenous dose of 4 mg based on a comparison of relative body surface areas).
Zoledronic acid is not shown to be genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay or in the Chinese hamster gene mutation assay with or without metabolic activation. Zoledronic acid is not reported to be genotoxic in the In vivo
rat micronucleus assay.
Impairment of Fertility:
Female rats when given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation showed the following effects in the high dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg based on AUC comparison) that included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg based on an AUC comparison) and high-dose group included an increase in pre-implantation loss and a decrease in the number of implantations and live fetuses.