Sign Out
Bone Modulator.
Pharmacology: Pharmacodynamics: Pharmacological Action: The principal pharmacological action of zoledronic acid is inhibition of 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 poptosis. It also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Pharmacokinetics: Distribution: Single- or multidose of 5- or 15-min infusions of zoledronic acid for injection 2, 4, 8 or 16 mg (4 times in 28 days) was given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process, showing population half-lives of t½α 0.24 hrs and t½β 1.87 hrs for the early distribution and elimination of the drug, and a terminal elimination half-life, t½γ of 146 hrs describing the low concentrations in plasma observed up to 28 days post-dose. Twenty-four (24) hrs after infusion, the concentration of drug in plasma is <1% of peak plasma concentration (Cmax).
Concentration-time curve (AUC0-24 hrs) in plasma is proportional to dose during the dose of 2-16 mg. Accumulation rate of zoledronic acid in triphase is low according to phase 1. The ratio of average AUC0-24 hrs of phase 2 and 3 relative to the phase 1 is 1.13±0.3 and 1.16±0.36, respectively. Binding to human plasma proteins was low (approximately 22%) and independent of the concentration of zoledronic acid.
Metabolism: Zoledronic acid does not inhibit human P-450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. The drug is primarily eliminated intact via the kidney.
Excretion: In a study in patients with cancer and bone metastases (n=64), 39±16% of the administered zoledronic acid dose was recovered in the urine within 24 hrs. Cumulative percentage of excretion in urine within 24 hrs is independent of dose. And the drug recovery in the urine has not met balance within 24 hrs. It is supposed that zoledronic acid first integrate with bone, then slowly released back into the systemic circulation. So long-term low concentration of drug is observed in plasma. The 0- to 24-hr renal clearance of zoledronic acid in these patients was 3.7±2 L/hr. The clearance of zoledronic acid is independent of dose, but related to creatinine clearance rate. In a study in patients with cancer, increasing the infusion time of a zoledronic acid 4-mg dose from 5 min (n=5) to 15 min (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion [(mean±SD) 403±118 ng/mL vs 264±86 ng/mL) and a 10% increase in the total AUC (378±116 ng x hr/mL vs 420±218 ng x hr/mL). The difference of AUC do not have statistical significance.
Toxicology: Genotoxicity: Ames test, Chinese hamster ovary cell chromosomal aberration test, Chinese hamsters gene mutation test and rats micronucleus test show negative reaction.
Reproductive Toxicity: Female rats were SC infused with Hendronic 0.01, 0.03, 0.1 mg/kg/day from 15 days before mating to the end of pregnancy (AUC were 0.07, 0.2, 1.2 times of those IV infused to people). Animals in high-dose group showed ovulation inhibition and conception rate decrease. Animals emerged loss increased before embryo implantation, amount of embryos, and decreased vivi-embryo and survival rate of newly born rats in both middle-dose group and high-dose group. Female rats appeared dystocia and increase in perinatal mortality from all groups of different doses. The death probably related to perinatal hypocalcemia caused by the inhibition of calcium mobilization in bone. It may be the common adverse reaction to diphosphonic acid drugs.
Female rats were SC infused with Hendronic 0.1, 0.2, 0.4 mg/kg/daily during pregnancy (AUC were 1.2, 2.4, 4.8 times of those IV infused with 4 mg to people). Animals emerged embryos loss increase before and after implantation, vivi-embryo reduction, skeleton abnormality, internal organs abnormality and appearance abnormality in middle-dose group and high-dose group.
The skeleton abnormality of animals from high-dose group appeared no ossification and incomplete ossification, skeleton cirrhosis and thickened, curved and shortened. Toxic reactions eg, crystalline lens minification, cerebellum hypoplasia, hepatic lobule minification or loss, lobe of lung deformation, vasodilatation, cleft palate, dropsy could be observed in high-dose group. Animals in low-dose group also have the adverse effect of skeleton abnormality. Animals in the high-dose group were observed weight and food consumption decline in the experiment. It implied that the experiment reached highest level of drug exposure.
Pregnant rabbits were SC infused with Hendronic 0.01, 0.03, 0.1 mg/kg/daily (AUC were not >0.5 times of those IV infused with 4 mg to people). Toxicity to newly born was not observed. Animals of each group (dose should not be <0.05 times of those IV infused with 4 mg to people according to the relative surface area) had some abortions and died incidents probably because of hypocalcemia caused by the drug.
Carcinogenicity: Mice and rats were used to proceed the conventional lifetime carcinogenic study. Mice were taking Hendronic 0.1, 0.5, 2 mg/kg/daily through oral administration (dose should not be <0.002 times of those IV infused with 4 mg to people according to the relative surface area). The animals' incidence of adenocarcinoma increased from medication administration teams. Rats were taking Hendronic 0.1, 0.5, 2 mg/kg/daily through oral administration (dose should not be <0.02 times of those IV infused with 4 mg to people according to the relative surface area). The increase of cancer incidence was not observed.
