Sign Out
Pharmacotherapeutic group: Bisphosphonate. ATC Code: M05B A08.
Pharmacology: Pharmacodynamics: The principal pharmacologic action of Zoledronic acid is inhibition of bone resorption. It is one of the most potent inhibitors of osteoclast bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, Zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid exerts direct antitumor effects on human myeloma and breast cancer cells inhibiting their proliferation and inducing apoptosis. Zoledronic acid is antiangiogenic in animal tumor model. This antitumor efficacy may be enhanced when used in combination with other anticancer drugs.
Clinical studies in patients with hypercalcaemia of malignancy (HCM) showed that single-dose infusions of Zoledronic acid are associated with decrease in serum calcium and phosphorus and increase in urinary calcium and phosphorus excretion. Normalisation of serum calcium by day 4 was greater for Zoledronic acid 4 mg and 8 mg doses than pamidronate.
Hypercalcaemia of Malignancy: Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcaemia of malignancy (HCM), tumor-induced hypercalcaemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcaemia. Reducing excessive bone resorption and adequate fluid administration are, therefore, essential to the management of hypercalcaemia.
Pharmacokinetics: Single or multiple (q 28 days) 5-minute infusion or 2,4,8 or 16mg Zoledronic acid were given to patients with cancer and bone metastases. The post infusion 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 <1% Cmax 24 hours post infusion with population half-lives of t1/2alpha 0.24 hours and t1/2beta 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of Zoledronic acid was 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of Zoledronic acid was dose proportional from 2 to 16 mg. The accumulation of Zoledronic acid measured over three cycles was low, with mean (AUC0-24h) ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.36, respectively.
In vitro and ex vivo studies showed low affinity of Zoledronic acid for the cellular components of human blood. Binding to human plasma proteins was approximately 22% and was independent of the concentration of Zoledronic acid.
Metabolism: Zoledronic acid does not inhibit P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose was found in the faces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney.
Excretion: In patients with cancer and bone metastases on average (± s.d.) 39 ± 16% of the administration Zoledronic acid was recovered in the urine within 24 hour, with only trace amounts of drug found in urine post day 2. In cumulative percentage of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulations, giving rise to the observed prolonged low plasma concentrations days 2 to 20 post dose. The 0-24 hour renal clearance of Zoledronic acid was on average 3.7 ± 2.0l/h.
Zoledronic acid clearance was reasonably independent of dose and demographic variables, with effects of bodyweight, gender and race, on clearance was dependent on creatinine clearance.
Special Populations: No pharmacokinetic data in patients with hypocalcaemia.
Pediatrics: No pharmacokinetics data in pediatric patients.
Geriatrics: The pharmacokinetics of Zoledronic acid were not affected by age in patients with cancer and bone metastases aged 38 years to 84 years.
Race: The pharmacokinetics of Zoledronic acid was not affected by race in patients with cancer and bone metastases.
Hepatic insufficiency: There are no pharmacokinetic data in patients with impaired liver functions. Zoledronic acid is not cleared by liver therefore impaired liver function may not affect the pharmacokinetic of Zoledronic acid.
Renal insufficiency: Patients with mild to moderate (creatinine 50-80ml/min) renal impairment showed an increase in plasma AUC of 26-27% whereas patients with moderate to severe renal impairment (creatinine clearance 30-50ml/min) showed an increase in plasma AUC of 27-41%. Limited pharmacokinetic data are available for Zoledronic acid in patients with severe renal impairment (creatinine clearance <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 10ml/min.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Zoledronic acid was administered orally (gavage) to rats and mice for at least 104 weeks without evidence of carcinogenic potential. Chronic parenteral administration was not feasible given the potential of the compound to cause severe local irritation.
Mutagenesis: 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 genotoxic in the vivo rat micronucleus assay.
Impairment of Fertility: 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 time 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.
