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Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates. ATC code: M05BA08.
Pharmacology: Pharmaodynamics: Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralisation or mechanical properties of bone.
In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anti-tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in the studies: In vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment, making it less conducive to tumour cell growth, anti-angiogenic activity and anti-pain activity.
In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti-adhesion/invasion activity.
Pharmacokinetics: Biotransformation: 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.
Elimination: Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½γ 146 hours. Zoledronic acid is not metabolized 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. The total body clearance is 5.04 ± 2.5 l/h, independent of dose. Increasing the infusion time from 5 to 15 minutes causes 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.
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes and the administered dose was recovered in the feces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.
The renal clearance of zoledronic acid was correlated with creatinine clearance. Only limited pharmacokinetic data are available in patients with severe renal insufficiency.
Zoledronic acid showed low affinity 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. 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.
Special populations: Paediatric patients: Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level.
