Pamidronate Disodium Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Pamidronate Disodium Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Breast Cancer, Bone Metastases, Hypercalcemia of Malignancy, Hypercalcemia, Osteolytic Bone Lesions of Multiple Myeloma, Paget's Disease
Class: Bisphosphonates
Form: Liquid solution, Intravenous (IV)
Ingredients: Pamidronate disodium, Mannitol, Phosphoric Acid, Sodium Hydroxide, Water for Injection.

Pharmaceutical Information

Drug Substance

Proper name: Pamidronate Disodium, PPC
Chemical name: Disodium-3-amino-l-hydroxypropylidene-1,1-bisphosphonate
Molecular formula and molecular mass: C3H9NO7P2Na2sub>• 5H2O
369.1
Structural formula:
Pamidronate disodium (prepared in situ from pamidronic acid)
Physicochemical properties
Description: Colourless, crystalline powder
Solubility: Soluble in water or 2N sodium hydroxide, poorly soluble in 0.1N hydrochloric acid and 0.1N acetic acid and insoluble in organic solvents
pH: The pH of a 1% solution in water is approximately 8.2.

Clinical Trials

The potent inhibitory effect of pamidronate disodium on bone resorption has been demonstrated in clinical studies which have shown pamidronate disodium to be highly effective in the treatment of malignant hypercalcemia, bone metastases and Paget’s disease of the bone.

Tumour-Induced Hypercalcemia

Pamidronate disodium lowered plasma calcium between 3 to 7 days following the initiation of treatment irrespective of the tumour type or presence of detectable bone metastases. In controlled clinical trials, pamidronate disodium was infused at up to 15 mg per hour for doses up to 60 mg whereas 90 mg was infused over 24 hours.

Normalization of plasma calcium levels was accompanied by a decrease in urinary calcium levels to normal, and in some cases, to below normal levels. Since it has been reported that calcium absorption from the kidney and gut are not increased by pamidronate disodium administration, the decreases in urinary calcium observed can be regarded as solely reflecting inhibition of bone resorption rather than effects on the kidney and gut.

Normalization of plasma calcium, including transient hypocalcemia, is dependent on the initial levels of plasma calcium and the dose of pamidronate disodium selected. Severe hypercalcemia (plasma calcium > 4.0 mmol/L) required higher doses of pamidronate disodium for normalization than moderate hypercalcemia. However, treatment of moderate hypercalcemia with high doses of pamidronate disodium (60 to 90 mg) can lead to transient hypocalcemia. A single infusion of 90 mg is indicated only for cases of severe hypercalcemia.

Several changes in biochemical parameters occur secondary to the normalization of plasma calcium which reflect the antiresorptive activity of pamidronate disodium. Parathyroid hormone levels, which are usually suppressed in hypercalcemia of malignancy, typically recover after treatment with pamidronate disodium. This is considered to be a physiological response to the lowering of blood calcium levels. Previously suppressed parathyroid hormone levels have not been observed to increase above the upper limits of normal.

Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal after treatment with pamidronate disodium. These changes occur within the first week after treatment, as do decreases in serum calcium levels, and are consistent with the antiresorptive pharmacologic action of pamidronate disodium.

The decrease in urinary phosphate excretion despite a rise in glomerular filtration rate (GFR) after pamidronate disodium administration suggests a positive phosphorus balance. This effect may be related to increased phosphate uptake into bone since the lowering of phosphate excretion occurred after reductions in plasma calcium, plasma phosphate, and urinary hydroxyproline. Phosphate levels usually returned to normal within 7 – 10 days. The ratio of plasma phosphate to the renal phosphate threshold (TmPO4/GFR) is also decreased with pamidronate disodium treatment, probably reflecting a rise in PTH secretion due to the sharp fall in plasma calcium.

Pamidronate disodium had no consistent effects on plasma magnesium levels, thus confirming the absence of effect of pamidronate disodium on magnesium metabolism.

Bone Metastases and Multiple Myeloma

Three large Phase III trials, one in multiple myeloma and two in breast cancer (one versus standard chemotherapy and one versus hormonal therapy) showed that 90 mg Pamidronate Disodium for Injection infused every 3 – 4 weeks significantly decreased the skeletal morbidity rate (number of SREs/year) in all patient groups (see below for a more detailed description of the results). Skeletal-related events (SREs) were defined as episodes of pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression. Radiation to bone was also significantly lower in all pamidronate disodium for injection groups. The proportion of patients experiencing an SRE was significantly smaller, and the time to first SRE was significantly longer in pamidronate disodium for injection-treated multiple myeloma and breast cancer + chemotherapy patients. The same trend was seen in the hormonally-treated breast cancer patients. Fewer pamidronate disodium for injection-treated multiple myeloma patients suffered vertebral pathologic fractures.

Multiple Myeloma

In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma were enrolled to receive pamidronate disodium for injection or placebo in addition to their underlying antimyeloma therapy to determine the effect of pamidronate disodium for injection on the occurrence of skeletal-related events (SREs). SREs were defined as episodes of pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression. Patients received either 90 mg of pamidronate disodium for injection or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the 392 patients, 377 were evaluable for efficacy (196 pamidronate disodium for injection, 181 placebo). The proportion of patients developing any SRE was significantly smaller in the pamidronate disodium for injection group (24% vs 41%, p < 0.001), and the mean skeletal morbidity rate (# SRE/year) was significantly smaller for pamidronate disodium for injection patients than for placebo patients (mean: 1.1 vs 2.1, p < 0.02). The times to the first SRE occurrence, pathologic fracture, and radiation to bone were significantly longer in the pamidronate disodium for injection group (p = 0.001, 0.006, and 0.046, respectively). Moreover, fewer pamidronate disodium for injection patients suffered any pathologic fracture (17% vs 30%, p = 0.004) or needed radiation to bone (14% vs 22%, p = 0.049).

In addition, decreases in pain scores from baseline occurred at the last measurement for those pamidronate disodium for injection patients with pain at baseline (p = 0.026) but not in the placebo group. At the last measurement, a worsening from baseline was observed in the placebo group for the Spitzer quality of life variable (p < 0.001) and ECOG performance status (p < 0.011) while there was no significant deterioration from baseline in these parameters observed in pamidronate disodium for injection-treated patients.

After 21 months, the proportion of patients experiencing any skeletal event remained significantly smaller in the pamidronate disodium for injection group than the placebo group (p = 0.015). In addition, the mean skeletal morbidity rate (# SRE/year) was 1.3 vs 2.2 for pamidronate disodium for injection patients vs. placebo patients (p = 0.008), and time to first SRE was significantly longer in the pamidronate disodium for injection group compared to placebo (p = 0.016). Fewer pamidronate disodium for injection patients suffered vertebral pathologic fractures (16% vs 27%, p = 0.005). Survival of all patients was not different between treatment groups.

Bone Metastases

Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of pamidronate disodium for injection infused over two hours every three to four weeks for 24 months to that of placebo in preventing SREs in breast cancer patients with osteolytic bone metastases who had at least two lytic metastases, one of which was at least 1 cm in diameter. In one trial, patients were receiving hormonal therapy, and in the second, patients were being treated with chemotherapy at trial entry.

Breast Cancer Patients Receiving Hormonal Therapy

372 patients receiving hormonal therapy were randomized to receive either 90 mg of pamidronate disodium for injection (182) or placebo (190), each given as a two-hour infusion at intervals of three to four weeks for 24 months. The proportion of patients developing an SRE was smaller in the pamidronate disodium for injection treatment group than in the placebo treatment group throughout the trial (3, 6, 9, 12, 15, 18, 21 and 24 months). At the end of the 24 monthly cycles of the trial, the proportion of patients having an SRE (+HCM) was significantly lower for pamidronate disodium for injection patients than for placebo patients (56% vs 67%, p = 0.027) and the mean skeletal morbidity rate (# SRE/year) was significantly smaller for pamidronate disodium for injection patients than for placebo patients (mean: 2.4 vs 3.8, p = 0.008). The median time to the first SRE (+HCM) and for radiation to bone significantly greater for pamidronate disodium for injection patients compared to placebo patients (p = 0.049 and 0.016, respectively).

Bone lesion partial response, assessed radiologically, was 30% for the pamidronate disodium for injection group and 24% for the placebo group (p = 0.202). In addition, pain and analgesic scores increased significantly less (p = 0.007, and p < 0.001, respectively) from baseline in the pamidronate disodium for injection group than in the placebo group at last measurement.

Breast Cancer Patients Receiving Chemotherapy

382 patients receiving chemotherapy were randomized to receive either 90 mg of pamidronate disodium for injection (n = 185) or placebo (n = 197), each given as a two-hour infusion at intervals of three to four weeks for 24 months. The proportion of patients developing any SRE was significantly lower on pamidronate disodium for injection than on placebo at 15 months, 18 months, 21 months and 24 months. At the end of the 24 monthly cycles of the trial, the proportion of patients having any SRE (+HCM) was significantly lower for pamidronate disodium for injection patients than for placebo patients (50% vs. 70%, p < 0.001) and the mean skeletal morbidity rate (# SRE/year) was significantly smaller for pamidronate disodium for injection patients than for placebo patients (mean: 2.6 vs 4.3, p < 0.001). The times to the first SRE occurrence, any pathologic fracture, non-vertebral pathologic fracture, and radiation to bone was statistically significantly shorter for placebo compared to pamidronate disodium for injection patients (p < 0.001, 0.009, 0.001, and 0.001, respectively).

Bone lesion complete and partial response, assessed radiologically, was significantly higher in pamidronate disodium for injection vs placebo breast cancer patients receiving chemotherapy (34% vs 19%, p = 0.002). In addition, pain and analgesic scores increased significantly less (p = 0.050 and p = 0.009, respectively) from baseline in the pamidronate disodium for injection group than in the placebo group at last measurement. In both treatment groups, the ECOG performance status worsened from baseline to endpoint, but the worsening was significantly (p = 0.002) larger in the placebo group than in the pamidronate disodium for injection group.

Paget’s disease

A clear dose response was demonstrated in a randomized, double-blind clinical trial in which patients received a single dose of pamidronate disodium (N = 64). A single infusion of pamidronate disodium 15 mg was not effective; 90 mg was most effective. A 50% fall from baseline was achieved in both ALP (alkaline phosphatase) and OHP:Cr (hydroxyproline:creatinine ratio) in > 20% of patients with both 45 and 90 mg pamidronate disodium (p < 0.05).

In a multiple-dose infusion study, pamidronate disodium was infused i.v. at 15 mg/2 hours daily for 5 consecutive days (N = 12). ALP normalized in 4 patients. Five patients required retreatment within 6 months and 6 patients after 6 months.

In an open clinical trial, patients were stratified according to initial ALP. Those with ALP < 500 I.U./L (Group A; N = 65) or > 500 I.U./L (Group B; N = 11) were administered 180 – 195 mg or 360 – 375 mg pamidronate disodium, respectively, as 30 mg weekly infusions. In Group A, ALP normalized in 80% and OHP:Cr in 88% patients. In addition, bone scan results significantly improved. The duration of remission was 543 and 388 days, respectively. In Group B, ALP and OHP:Cr were reduced 80% and 73%, respectively. These patients had particularly severe disease and only 25% remitted on the basis of OHP:Cr and the median duration of remission was relatively short (52 days). In both groups, there were subjective clinical improvements in over 50% patients.

In a larger, open clinical trial of similar design, patients were also stratified according to initial ALP. However, those with ALP < 500 I.U./L (Group A; N = 159) or > 500 I.U./L (Group B; N = 52) were administered 210 mg or 390 mg pamidronate disodium, respectively, as infusions of 30 mg initially then 60 mg every 2 weeks. In Group A, ALP normalized in 81% and OHP:Cr in 93% patients. In addition, bone scan results significantly improved (scintigraphic index, % of skeleton affected and number of bones affected). The median duration of remission was 780 and 494 days, respectively. In Group B, results were similar to those achieved in the previous study. Symptom evaluation demonstrated improvement in 50 – 60% patients.

Detailed Pharmacology

Animal Pharmacology

Subcutaneous administration of pamidronate disodium to rats reduced urinary hydroxyproline excretion within 2 – 8 days starting at 0.16 μmol/kg/day and reaching a maximum at 16 μmol/kg/day. At higher doses (> 40 μmol/kg/day) pamidronate disodium inhibited bone mineralization as assessed by the molar ratio of calcium to hydroxyproline in metaphyseal bone. Doses below this level reduced bone alkaline phosphatase activity, hydroxyproline synthesis and calcium content. These changes in bone apposition parameters required at least 23 days exposure for a maximal effect, compared to 8 days for effects on bone resorption. Thus, pamidronate disodium inhibits bone resorption in rats at doses several-fold lower than those that affect bone growth and mineralization.

Low doses of pamidronate disodium increased both elastic and ultimate bone strength in the rat, whereas high doses (> 14 mg/kg/day i.p.) produced opposite effects. The latter doses were far above those required to completely suppress calcium mobilization in rats.

In dogs, long-term intermittent treatment with pamidronate disodium retains structural integrity in cortical and vertebral bone. Intermittent oral pamidronate disodium treatment for 12 weeks caused no changes in the mechanical properties of cortical femoral bone but trabecular bone showed a significant increase in compressive stiffness and torsional strength.

In mice, s.c. administration of 16 μmol/kg (4.5 mg/kg) pamidronate disodium for 7 days increased tibial growth plate width without concomitant effects on longitudinal growth.

The intermittent administration of pamidronate disodium to animals was also effective in inhibiting bone resorption. In 10-week old pigs, administration of 1.6 μg/kg/day pamidronate disodium for 5 out of 21 days produced a significant inhibition of bone resorption that was equivalent to that produced with a continuous 60-day dosing regimen. In mice, once weekly treatment for 1 year augmented diaphyseal wall thickness and the number of persisting trabeculae. This effect was mainly achieved by a suppression of endosteal bone resorption, which occurs during the retrogressive phase of C57BL/Silberberg mice aged more than 4 months. Bones of treated mice also demonstrated a higher femoral calcium content and ash weight, and increased resistance to fracture stress in comparison to untreated controls.

As a result of hormonal regulation, pamidronate disodium does not significantly affect serum calcium in normal, healthy animals. Under various experimental conditions however, changes in serum calcium values will reflect the effects of pamidronate disodium on bone metabolism. In thyroid-parathyroidectomized rats, the 1,25(OH)2 vitamin D3-stimulated mobilization of calcium from bone was inhibited by pamidronate disodium at daily doses of 0.02 – 0.6 mg/kg s.c. Similarly, pamidronate disodium reduced hypercalcemia of malignancy in rats bearing Walker 256 carcinosarcoma tumours. Mice bearing 5T2 myelomas had fewer skeletal lesions if treated with pamidronate disodium, although the myeloma itself was unaffected by pamidronate disodium treatment.

Twenty-four hours after single intravenous administration of 10 mg/kg to growing rats, approximately 50% of the dose is retained in bone, 0.1% in blood, 1.1% in spleen and 30% in liver. Pamidronate disodium is also stored in tracheal cartilage of rats. The percent uptake into the liver increases with dose, ranging from 3.0% at 0.01 mg/kg, to 30% at 10 mg/kg doses.

Levels accumulated in liver at 10 mg/kg gradually decline during the 2 weeks after administration, with redistribution and uptake into bone, or elimination by the kidneys over 24 – 48 hours.

Pamidronate disodium does not undergo significant metabolism in the rat: at 10 mg/kg i.v., approximately 20% of the dose is excreted unchanged in the urine by 24 hours. Bile accounts for less than 0.1% of the administered dose. The biological half-life of pamidronate disodium in rats has been estimated to be approximately 300 days.

A preferential uptake and prolonged storage of 14C-pamidronate disodium in bone is also observed in dogs following single intravenous administration. Radioactivity is detectable in blood only up to 72 hours.

Human Pharmacology

Pamidronate disodium is a second-generation bisphosphonate. These agents are synthetic analogues of pyrophosphate and specifically inhibit bone resorption. First generation compounds such as 1-hydroxyethylidene-1,1-biphosphonic acid (HEBP or etidronate disodium) block resorption but may also inhibit bone mineralization. Pamidronate disodium, a second generation bisphosphonate, inhibits bone resorption at doses that do not appear to affect the mineralization of newly-formed osteoid tissue and thus constitutes a rational treatment for pathological bone resorption. The predominant mode of action appears to be a local, direct effect; bisphosphonates complex tightly to, and inhibit the formation and dissolution of, hydroxyapatite crystals.

Toxicology

Acute Toxicity

In acute toxicity studies, pamidronate disodium was better tolerated when administered as a short-term i.v. infusion or i.p. than as a bolus i.v. dose, presumably because of lower plasma concentrations. In mice, the i.v. bolus and i.p. LD50 of pamidronate disodium were 20.3 mg/kg and 40 mg/kg respectively; in rats 80 mg/kg and 65 mg/kg, and in rabbits, 18.5 mg/kg and 190 mg/kg. In dogs, the LD50 was > 10 mg/kg for a bolus i.v. dose and > 40 mg/kg when administered as an i.v. infusion.

Subacute and Chronic Toxicity

Pamidronate disodium has been administered to mice, rats, rabbits and dogs for ≤ 3 months by intermittent i.v. infusion or a bolus i.v. dose. Repeat dose animal studies demonstrate that intermittent administration of pamidronate disodium by i.v. infusion is better tolerated than the bolus i.v. route. Dose- and regimen-dependent nephropathy occurred in all species except the mouse. These studies indicate that adverse effects with pamidronate disodium correlate strongly with peak plasma concentration. It should therefore be administered intermittently by slow infusion; daily intravenous administration, especially as a bolus, should be avoided.

The no-toxic effect level for rats and dogs administered 2, 6 or 20 mg/kg by i.v. infusion for 1 hour weekly for 3 months was 2 mg/kg for both species. In all dose groups in the dog, but only at the highest dose in the rat, pharmacological effects were evident as non-reversible, dose- related increase in primary spongy bone formation with a widened metaphyses, increased calcification and impaired remodeling with no impairment of mineralization. This was accompanied by reduced AP and serum phosphate. The major target organ for toxic effects was the kidney, but following high i.v. doses, especially those administered as a bolus, inflammation/degeneration was also observed in the stomach and the lung, and to a lesser extent in the spleen, liver and heart.

Reproductive Toxicity

Pamidronate crosses the placenta barrier readily and accumulates primarily in the fetal bones in rats. Reproductive toxicological studies conducted in rats and rabbits by peroral or intravenous administration at dose levels comparable to human therapeutic dose revealed that pamidronate causes the following adverse events and developmental abnormalities: reduced fertility in both sexes and the first generation of the offspring, distress and prolongation of parturition process with fatal outcome, marked increases in resorption, pre- and post-implantation losses, reduced number of viable pups born, delayed skeletal maturation and ossification, shortening of long bones and visceral and external abnormality (dilated and kinked ureters, displaced testis, shortened body, curved or hooked joints, mal-rotated hind limbs, subcutaneous hemorrhage and edema, etc.).

Carcinogenesis and Mutagenesis

Mutagenic potential was assessed by three different methods both in vitro (Ames test, point mutation test, and a cytogenetic test) and in vivo (nucleus anomaly test, sister chromatid exchange study and a micronucleus test). There was no evidence of mutagenic potential in vivo.

In vitro tests were also negative apart from a slight increase in the number of chromosome aberrations in Chinese hamster ovary cells at the highest concentration only (2500 μg/mL).

Carcinogenic potential was assessed in both mice and rats treated with pamidronate disodium ≤ 40 mg/kg/day and ≤ 75 mg/kg/day, respectively, by gavage for 2 years. These studies repeated earlier studies completed in the 1970’s, in which pamidronate disodium ≤ 1000 mg/kg was added to the food supply. From these studies, pamidronate disodium does not appear to have carcinogenic potential.

The only unexpected finding in these repeat carcinogenicity studies was hydrocephaly observed in the mouse study. This event occurred at all dose levels, and was probably caused by changes in cranial bones as a result of the pharmacological activity of the compound in the young, growing animals. It is not thought to be of relevance in adult patients in whom bone growth is complete.

In mice receiving pamidronate disodium ≤ 40 mg/kg daily, there was dose-dependent reduction in the incidence of neoplasms, which was attributed to pamidronate disodium-related decreases in food consumption; mice fed a restricted diet have been shown to develop fewer tumours than those fed ad libitum. In this study, the incidence of liver tumours was reduced relative to control animals. In female mice fed with pamidronate disodium 879 mg/kg/day in the diet, the incidence of benign hepatomas was increased relative to control animals.

In both rat carcinogenicity studies, the incidence of neoplastic lesions was within the range observed with historical controls, apart from a slight increase in intestinal leiomyomas observed in females in one study only. Intestinal leiomyomas occur spontaneously in 0.44% Wistar rats (range 0 – 2%) used as controls in carcinogenicity studies. The mean incidence of these tumours in female Wistar rats administered 1000 mg/kg/day in the diet was 1.2% (range 0 – 3.7%). As no intestinal leiomyomas were observed in female rats in the other rat study, it is unlikely that these benign, non-fatal tumours are of biological or clinical significance.