Pharmacology: Pamidronate Disodium is a potent inhibitor of osteoclastic bone resorption. It binds strongly to hydroxyapatite crystals and inhibits the formation and dissolution of these crystals in vitro. Inhibition of osteoclastic bone resorption in vivo may be at least partly due to binding of the drug to be bone mineral.
Pamidronate Disodium suppresses the accession of osteoclastic precursors on to the bone and their subsequent transformation into the mature, resorbing osteoclasts. However, the local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the predominant mode of action in vitro and in vivo.
Experimental studies have demonstrated that Pamidronate Disodium inhibits tumour-induced osteolysis when given prior to or at the time of inoculation or transplantation with tumour cells. Biochemical changes reflecting the inhibitory effect of Pamidronate Disodium on tumour-induced hypercalcaemia, are characterized by a decrease in serum calcium and phosphate and secondarily by decrease in urinary excretion of calcium, phosphate and hydroxyproline.
Pharmacokinetics: General Characteristics: Pamidronate Disodium has a strong affinity for calcified tissues and total elimination of Pamidronate Disodium from the body is not observed within the time frame of experimental studies. Calcified tissues are, therefore, regarded as site of apparent elimination.
Absorption: Pamidronate Disodium is given by IV infusion. By definition, absorption is complete at the end of the infusion.
Distribution: Plasma concentrations of Pamidronate Disodium rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent half-life in plasma is about 0.8 hr. Apparent steady-state concentrations are therefore achieved with infusions of more than about 2-3 hrs duration. Peak plasma Pamidronate Disodium concentrations of about 10nmol/mL are achieved after an IV infusion of 60 mg given over 1 hr.
In animals and in man, a similar percentage of the dose is retained in the body after each dose of Pamidronate Disodium. Thus, the accumulation of Pamidronate Disodium in bone is not capacity-limited and is dependent solely on the total cumulative dose administered.
The percentage of circulating Pamidronate Disodium bound to plasma proteins is relatively low (about 54 %) and increases when calcium concentrations are pathologically elevated.
Metabolism: Pamidronate Disodium is not metabolized and is exclusively eliminated by renal excretion.
Excretion: Pamidronate Disodium does not appear to be eliminated by biotransformation and it is almost exclusively eliminated by renal excretion. After an IV infusion, about 20-55% of the dose is recovered in the urine within 72 hours as unchanged Pamidronate Disodium.
Renal Insufficiency: A pharmacokinetic study conducted in patients with cancer showed no differences in plasma AUC of Pamidronate Disodium between patients with normal renal function and patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30mL/min), the AUC of Pamidronate Disodium was approximately 3 times higher than in patients with normal renal function (creatinine clearance >90mL/min).
Hepatic Insufficiency: The pharmacokinetics of Pamidronate Disodium were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a single 90 mg dose of Pamidronate Disodium infused over 4 hours. Although there was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (39.7%) and Cmax (28.6%) values. Nevertheless, Pamidronate Disodium was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after drug infusion. Because Pamidronate Disodium is administered on a monthly basis, drug accumulation is not expected. No changes in Pamidronate Disodium dosing regimen are recommended for patients with mild to moderate abnormal hepatic function.