12.3 Pharmacokinetics
Pharmacokinetic data in patients with hypercalcemia are not available.

Distribution

Single or multiple (q28days) 5-minute or 15-minute infusions of 2, 4, 8 or 16mg Zometa were given to 64patients with cancer and bone metastases. The postinfusion decline of zoledronicacid 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 24hours postinfusion with population half-lives of t1/2α 0.24hours and t1/2β 1.87hours for the early disposition phases of the drug. The terminal elimination phase of zoledronicacid was prolonged, with very low concentrations in plasma between Days2 and 28 postinfusion, and a terminal elimination half-life t 1/2γ of 146hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronicacid was dose proportional from 2-16mg. The accumulation of zoledronicacid 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 zoledronicacid for the cellular components of human blood. Invitro, mean zoledronicacid protein binding in human plasma ranged from 28% at 200ng/mL to 53% at 50ng/mL.

Metabolism

Zoledronicacid does not inhibit human P450enzymes invitro. Zoledronicacid does not undergo biotransformation invivo. 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 20nCi 14C-zoledronicacid 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 zoledronicacid is not metabolized.

Excretion

In 64patients with cancer and bone metastases, on average (±s.d.) 39±16% of the administered zoledronicacid dose was recovered in the urine within 24hours, with only trace amounts of drug found in urine post-Day2. The cumulative percent of drug excreted in the urine over 0-24hours was independent of dose. The balance of drug not recovered in urine over 0-24hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24hour renal clearance of zoledronicacid was 3.7±2.0L/h.

Zoledronicacid 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 zoledronicacid from 5minutes (n=5) to 15minutes (n=7) resulted in a 34%decrease in the zoledronicacid concentration at the end of the infusion ([mean±SD] 403±118ng/mL versus 264±86ng/mL) and a 10%increase in the total AUC (378±116ngxh/mL versus 420±218ngxh/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 zoledronicacid were not affected by age in patients with cancer and bone metastase