DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Zometa (Zoledronic Acid) - Description and Clinical Pharmacology

 
 



  DESCRIPTION

Zometa contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is

      Zoledronic acid is a white crystalline powder. Its molecular formula is C5H10N2O7P2 • H2O and its molar mass is 290.1g/Mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.0.

      Zometa is available in vials as a sterile liquid concentrate solution for intravenous infusion. Each 5-mL vial contains 4.264 mg of zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis.

      Inactive Ingredients: mannitol, USP, as bulking agent, water for injection and sodium citrate, USP, as buffering agent.

  CLINICAL PHARMACOLOGY

Mechanism of Action

The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. 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.

Pharmacodynamics

Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zometa are associated with decreases in serum calcium and phosphorus and increases 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 [ see Dosage And Administration (2) ] .

Pharmacokinetics

Pharmacokinetic data in patients with hypercalcemia are not available.

Distribution

Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Zometa were given to 64 patients with cancer and bone metastases. The postinfusion 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 postinfusion with population half-lives of t1/2α 0.24 hours and t1/2β 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 postinfusion, and a terminal elimination half-life t 1/2γ 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 showed 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.

Metabolism

Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose was 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 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.

Excretion

In 64 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 was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.

Special Populations

      Pediatrics

      Zometa is not indicated for use in children [ see Pediatric Use (8.4) ].

      Geriatrics

      The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years.

      Race

      Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases.

      Hepatic Insufficiency

      No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.

      Renal Insufficiency

      The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zometa in patients with severe renal impairment (creatinine clearance <30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:

CrCl = [140-age (years)] x weight (kg) {x 0.85 for female patients}

[72 x serum creatinine (mg/dL)]

      Zometa systemic clearance in individual patients can be calculated from the population clearance of Zometa, CL (L/h)=6.5(CLcr/90)0.4. These formulae can be used to predict the Zometa AUC in patients, where CL = Dose/AUC0-∞. The average AUC0-24 in patients with normal renal function was 0.42 mg•h/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of Zometa. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [ see Warnings And Precautions (5.2) ].

  NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females 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). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas).

Mutagenesis

Zoledronic acid was not 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 was not genotoxic in the in -vivo rat micronucleus assay.

Impairment of Fertility

Female rats were 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. Effects observed 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) 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 preimplantation losses and a decrease in the number of implantations and live fetuses.

  CLINICAL STUDIES

Hypercalcemia of Malignancy

Two identical multicenter, randomized, double-blind, double-dummy studies of Zometa 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zometa 4 mg given as a 5 -minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15 -minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [ see Warnings And Precautions (5.1, 5.2) and Dosage And Administration (2.4) ]. The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.

      In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of ≥12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to ≤10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.

      To assess the effects of Zometa versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zometa 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zometa 8 mg over Zometa 4 mg; however, the risk of renal toxicity of Zometa 8 mg was significantly greater than that seen with Zometa 4 mg.

     

Figure 1

Figure 1

      Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value <11.6 mg/dL (<2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zometa 4 mg and pamidronate 90 mg are shown in Table 10.

Table 10: Secondary Efficacy Variables in Pooled HCM Studies
Zometa 4 mg Pamidronate 90 mg
Complete Response N Response Rate N Response Rate
By Day 4 8645.3%9933.3%
By Day 7 8682.6%*9963.6%
Duration of Response N Median Duration (Days) N Median Duration (Days)
Time to Relapse 8630*9917
Duration of Complete Response 76326918
* P less than 0.05 versus pamidronate 90 mg.

14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors

Table 11 describes an overview of the efficacy population in three randomized Zometa trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zometa effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zometa is beneficial. The optimal duration of Zometa administration is not known.

      The studies were amended twice because of renal toxicity. The Zometa infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zometa treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zometa 8 mg group are not included in these analyses.

Table 11: Overview of Efficacy Population for Phase III Studies
Patient Population No. of Patients Zometa Dose Control Median Duration (Planned Duration) Zometa 4 mg
Multiple myeloma or metastatic breast cancer1,6484 and 8* mg
Q3-4 weeks
Pamidronate 90 mg
Q3-4 weeks
12.0 months
(13 months)
Metastatic prostate cancer6434 and 8* mg
Q3 weeks
Placebo10.5 months
(15 months)
Metastatic solid tumor other than breast or prostate cancer7734 and 8* mg
Q3 weeks
Placebo3.8 months
(9 months)
* Patients who were randomized to the 8 mg Zometa group are not included in any of the analyses in this package insert.

      Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zometa placebo-controlled studies are given in Table 12.

Table 12: Zometa Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors
I. Analysis of Proportion of Patients with a SRE 1 II. Analysis of Time to the First SRE
Study Study Arm &
Patient Number
Proportion Difference 2
& 95% CI
P-value Median
(Days)
Hazard Ratio 3
& 95% CI
P-value
Prostate Cancer Zometa 4 mg
(n=214)
33%-11%
(-20%, -1%)
0.02Not Reached0.67
(0.49, 0.91)
0.011
Placebo
(n=208)
44%321
Solid Tumors Zometa 4 mg
(n=257)
38%-7%
(-15%, 2%)
0.132300.73
(0.55, 0.96)
0.023
Placebo
(n=250)
44%163
1SRE=Skeletal-Related Event
2Difference for the proportion of patients with a SRE of Zometa 4 mg versus placebo.
3Hazard ratio for the first occurrence of a SRE of Zometa 4 mg versus placebo.

      In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zometa to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zometa compared to pamidronate are given in Table 13.

Table 13: Zometa Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer
I. Analysis of Proportion of Patients with a SRE 1 II. Analysis of Time to the First SRE
Study Study Arm &
Patient Number
Proportion Difference 2
& 95% CI
P-value Median
(Days)
Hazard Ratio 3  
& 95% CI
P-value
Multiple Myeloma
& Breast Cancer
Zometa 4 mg
(n=561)
Pamidronate
(n=555)
44%
46%
-2%
(-7.9%, 3.7%)
0.46373
363
0.92
(0.77, 1.09)
0.32
1SRE=Skeletal-Related Event
2Difference for the proportion of patients with a SRE of Zometa 4 mg versus pamidronate 90 mg.
3Hazard ratio for the first occurrence of a SRE of Zometa 4 mg versus pamidronate 90 mg.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2014