Zoledronic Acid (Page 5 of 7)

12.3 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 zoledronic acid 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 less than 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 t1/2γ of 146 hours. The area under the plasma concentration versus time curve (AUC0 to 24h ) of zoledronic acid was dose proportional from 2 to 16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0 to 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, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro , the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.

Metabolism
Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 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 14 C-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 to 24 hours was independent of dose. The balance of drug not recovered in urine over 0 to 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 to 24 hour renal clearance of zoledronic acid was 3.7 ± 2 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 × h/mL versus 420 ± 218 ng × h/‌mL). The difference between the AUC means was not statistically significant.

Special Populations
Pediatrics
Zoledronic acid 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 zoledronic acid in patients with severe renal impairment (creatinine clearance less than 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:

Cockcroft-Gault formula
(click image for full-size original)

Zoledronic acid systemic clearance in individual patients can be calculated from the population clearance of zoledronic acid, CL (L/h)=6.5(CLcr/90)0.4. These formulae can be used to predict the zoledronic acid AUC in patients, where CL = Dose/‌AUC0-∞. The average AUC0 to 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 zoledronic acid. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [see Warnings and Precautions (5.2)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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 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).

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.

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.

14 CLINICAL STUDIES

14.1 Hypercalcemia of Malignancy

Two identical multicenter, randomized, double-blind, double-dummy studies of zoledronic acid 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 zoledronic acid 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 zoledronic acid 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions ( 5.1 and 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 greater than or equal to 12 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 less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.

To assess the effects of zoledronic acid 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 zoledronic acid 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for zoledronic acid 8 mg over zoledronic acid 4 mg; however, the risk of renal toxicity of zoledronic acid 8 mg was significantly greater than that seen with zoledronic acid 4 mg.

Figure 1 Proportion of Complete Responders by Day 10 in Pooled HCM Studies
(click image for full-size original)

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 less than 11.6 mg/dL (less than 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 zoledronic acid 4 mg and pamidronate 90 mg are shown in Table 10.

Table 10: Secondary Efficacy Variables in Pooled HCM Studies

Zoledronic Acid Injection 4 mg

Pamidronate 90 mg

Complete Response N Response Rate N Response Rate

By Day 4 By Day 7

8686

45.3%82.6%*

9999

33.3%63.6%

Duration of Response N

Median Duration (Days)

N

Median Duration (Days)

Time of Relapse Duration of Complete Response

8676

30*32

9969

1718

* P less than 0.05 versus pamidronate 90 mg.

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