Zoruxa Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Zoledronic acid is a potent inhibitor of bone resorption. It inhibits osteoclast proliferation and induces osteoclast apoptotic cell death. Its potency results from its high affinity for mineralized bone and especially for sites of high bone turnover. Zoledronic acid inhibits farnesyldiphosphate (FPP) synthase and in addition the cellular biosynthetic, FPP synthase-mediated mevalonate pathway.
In the absence of FPP synthase, FPP and geranyl di-phosphate are not produced, which results in the inhibition of the GTP-binding proteins prenylation in osteoclasts. Low levels of prenylated GTP-binding proteins inhibit osteoclast activity and induce osteoclast apoptosis. Furthermore, zoledronic acid may boost osteoblast differentiation and increase bone mineralization.
Pharmacokinetics: Zoledronic acid is not metabolized in humans and is excreted intact in the urine. It has minor or no effects on the cytochrome P450 enzyme system and therefore has no interaction with the drugs metabolized via cytochrome P450. Zoledronic acid binding to plasma proteins is 22%. Zoledronic acid concentration in plasma after the infusion decreases rapidly due to the increased absorption of the drug by the bone. However, small amounts of zoledronic acid can be detected in plasma several days after the infusion, representing the drug released gradually from the bone during bone turn-over.
The excretion of zoledronic acid by the kidney does not depend on the dose or the infusion time. The drug can be detected in urine in trace amounts up to 28 days after the infusion, although adequate amounts are present in urine only in the first 24 hours. The amount found in the urine in the first 24 hours post dose, however, represents just the one- or two-thirds of the total dose as a result of the increased binding of the drug to the bone.
Specific Populations: Pediatrics: Zoledronic acid is not indicated for use in children.
Geriatrics: No overall differences in safety and efficacy of zoledronic acid relative to younger adults; however, the incidence of acute-phase inflammatory reactions was less in geriatric patients with osteoporosis or Paget's disease of bone than in younger adults. Because of the greater frequency of impaired renal function in geriatric patients, the renal function should be monitored with particular care in this age group.
Hepatic Impairment: No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Impairment: No dosage adjustment is required in patients with a creatinine clearance of ≥ 35 mL/min. Zoledronic acid is contraindicated in patients with creatinine clearance < 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure.