ZOBONE Concentrate for solution for infusion Ref.[50459] Active ingredients: Zoledronic acid

Absorption

Single and multiple 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in patients with bone metastases reported the following pharmacokinetic data, which is dose independent. After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hours and <1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0,1% of peak prior to the second infusion of zoledronic acid on day 28. Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½α 0.24 and t_½β 187 hours, followed by a long elimination phase with a terminal elimination half-life of t_½γ 146 hours. There was no accumulation of zoledronic acid in plasma after multiple doses given every 28 days.

Metabolism and Elimination

Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 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 with a half-life of at least 167 hours. The total body clearance is 5,04 ± 2,5 L/h, independent of dose, and unaffected by gender, age, race, and body weight. Increasing the infusion time from 5 to 15 minutes 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. The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as reported with other bisphosphonates.

No pharmacokinetic data for zoledronic acid have been reported in patients with hypercalcaemia or in patients with hepatic insufficiency. It has been reported that zoledronic acid does not inhibit human P450 enzymes in vitro, reported no biotransformation and in animal studies <3% of the administered dose was recovered in the faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.

The renal clearance of zoledronic acid was reported to be correlated with creatinine clearance, renal clearance representing 75 ± 33 % of the creatinine clearance, which showed a mean of 84 ± 29 mL/min (range 22 to 143 mL/min) in cancer patients. Population analysis has reported that for a patient with creatinine clearance of 20 mL/min (severe renal impairment), or 50 mL/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, of that of a patient showing creatinine clearance of 84 mL/min. Only limited pharmacokinetic data are available in patients with severe renal insufficiency (creatinine clearance <30 mL/min).

Distribution

Zoledronic acid is approximately 22% bound to plasma proteins. Zoledronic acid shows low affinity or no affinity for the cellular components of blood and plasma protein binding is approximately 56% and independent of the concentration of zoledronic acid.