Chemical formula: C₅H₁₀N₂O₇P₂ Molecular mass: 272.09 g/mol PubChem compound: 68740
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.
The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.
Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
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 preclinical studies:
Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, 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 levels.
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. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone and excretion via the kidneys.
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. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. 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, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. 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.
No interaction studies with other medicinal products have been performed with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound medicinal products are unlikely.
The renal clearance of zoledronic acid was 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 the 64 patients studied. Small observed increases in AUC(0.24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of medicinal product with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50-80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of zoledronic acid in patients with severe renal impairment (creatinine clearance <35 ml/min) is contraindicated due to an increased risk of renal failure in this population.
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. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.
The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.
In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to 7 times the human therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were well-tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when given for 52 weeks.
Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, and at the site of intravenous administration. The clinical relevance of these findings is unknown. The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological antiresorptive activity.
Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was observed in rats at doses ≥0.2 mg/kg and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to decreased serum calcium levels.
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
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