Clasteon
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Clasteon - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Hypercalcemia, Osteolytic Bone Lesions of Multiple Myeloma
Class: Bisphosphonates, Bone resorption inhibitors
Form: Liquid solution, Intravenous (IV), Capsules
Ingredients: clodronate disodium, gelatin, indigotin, magnesium stearate, maize starch, sodium starch glycolate, talc, titanium oxide

Pharmaceutical Information

Clodronate disodium belongs to the group of bisphosphonates (formerly known as diphosphonates), which is characterized by two C-P bonds. Since these two bonds are bound to the same carbon atom to form a P-C-P bond, clodronate disodium is classified as a geminal bisphosphonate.

Drug Substance

Proper name: Clodronate Disodium
Chemical name: Anhydrous, clodronate disodium (as tetrahydrate)
Molecular formula and molecular mass: CH2Cl2Na2O6P2 . 4 H2O; 360.92
Structural formula:
Physicochemical properties:
Description: White to yellowish-white crystalline powder
Solubility: Water: Freely soluble
Methanol: Very slightly soluble
Ethanol: Practically insoluble
Acetone: Practically insoluble
pH:
(0.5% (m/v) in water)
3.8 to 4.8
PKAIII:
(25˚C, 0.02 mol/L in water)
5.84
PKa IV:
(25˚C, 0.02 mol/L in water)
8.68
Melting Point: Sintering observed just above 50°C. No melting is noted up to 250°C.

Clinical Trials

To date, results from several controlled clinical trials have shown that clodronate disodium can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients, clodronate disodium, given intravenously either as a single infusion or as repeated daily (300 mg/d) administrations, normalized serum calcium, usually 3 to 5 days after the onset of therapy. In responding patients, long-term oral maintenance treatment resulted in sustained normocalcemia. The dose range was 1600 - 3200 mg daily with treatment period extending up to 18 months.

In patients displaying a good response to clodronate disodium, the fall in plasma calcium is accompanied by an increase in the calcium regulating hormones, parathyroid hormone and 1,25- dihydroxyvitamin D3. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate disodium-treated patients.

The data supporting the clinical efficacy and safety of clodronate disodium for the indication of osteolysis is compiled from three (3) controlled and several non-controlled clinical trials. These studies report on the use of clodronate disodium in normocalcemic patients with osteolytic/osteoporosis/osteosclerosis, bone metastases. In total, 448 patients received clodronate disodium for periods ranging from several days to 18 months.

Efficacy in these studies was demonstrated by improvement in bone related parameters.

  • Incidence of vertebral fractures
  • Incidence of non-vertebral fractures
  • Progression of bone metastases/Incidence of new bone metastases
  • Biochemical parameters relating to bone metabolism (urinary calcium/creatine excretion, urinary hydroxyproline/creatine excretion and serum calcium levels and/or hypercalcemic episodes)

No serious side effects have been reported in cancer patients receiving oral clodronate disodium, except for the occasional occurrence of mild and transient gastrointestinal upset.

Detailed Pharmacology

Preclinical Pharmacodynamics

Inhibition of calcification - in vivo action

Bisphosphonates inhibit calcification in vivo. They have an inhibitory effect on various experimental soft tissue calcifications, including arteries, kidneys, skin, muscle and heart. This inhibitory action is found after administration of the bisphosphonate by either the parenteral or oral routes.

There is a close correlation between the inhibition of calcium phosphate formation in vitro by the various bisphosphonates and their inhibitory effect on ectopic calcifications in vivo. Thi sevidence has led to the conclusion that the inhibition of calcification in vivo is physicochemical in nature.

The inhibition of soft tissue calcification by bisphosphonates does not parallel the inhibition of hard tissue calcification. Clodronate disodium has been shown to be an excellent inhibitor of calcification in soft tissue, with only a slight effect on bone and cartilage. At doses of 46.6 mg/kg given subcutaneously, which corresponds to 10 mg/kg of phosphorous, clodronate disodium did not have any effect on normal bone calcification. By contrast, the equivalent dose of etidronate disodium corresponding to 10 mg/kg phosphorus always produced inhibition of normal bone calcification. The long-term administration (2 years) of etidronate disodium, even at lower doses (0.5 mg/kg s.c.), results in the inhibition of calcification and ultimately to fractures, which is not the case with clodronate disodium. Finally, at doses of 2.5 mg/kg s.c., clodronate disodium does not have any negative action on the healing of fractures, particularly on traction resistance, in dogs.

Inhibition of bone resorption

Bisphosphonates proved to be very powerful inhibitors of bone resorption when tested in a variety of conditions, both in vitro and in vivo.

Using different in vitro models it has been shown that bone resorption may be inhibited by binding to the mineral component of the bone matrix, preventing its resorption by osteoclasts. Studies with osteoclasts isolated from bone and incubated with clodronate disodium (10-5 to 10-9) show a dose dependant inhibition of bone resorption and supports the requirement of binding to the mineralized matrix.

In vivo models have shown clodronate disodium as able to inhibit bone lysis induced by different tumour models. High doses of clodronate disodium, reduce the number of osteoclasts induced by the tumour and therefore inhibit bone resorption without affecting bone formation (mineralization).

There is also evidence, that clodronate disodium may not only prevent osteolysis , but bone mass/strength may even increase depending on the total amount of drug administered.

Preclinical Pharmacokinetics

In animals, the intestinal absorption of clodronate disodium is low. It is reported to be 4 to 10% in rats and 10 to 55% in dogs. Absorption of bisphosphonates is generally higher in younger animals and in rats and chicken occurs predominantly in the small intestine. Bisphosphonates are not metabolized and are excreted unchanged in the urine.

Clinical Pharmacology

In man, the intestinal absorption of clodronate disodium after oral administration is low (1 to 3%). The absolute bioavailability is 1 to 2%. Of the quantity absorbed, about 80% is excreted within 24 hours via the kidney and the remaining 20% is bound to bone. Because of its high affinity for calcium phosphate, clodronate disodium acts selectively on bone. The binding of clodronic acid to bone structures occurs preferentially in regions of increased bone turnover (osteoclast activity). The drug is not metabolized but is excreted unchanged in the urine.

After i.v. dose, clodronate disodium exhibits a plasma concentration profile which fits a twocompartment model with a T½α approximately 0.3 h and a t½β approximately 2 h, and terminal elimination phase with t½ approximately 13 h. The latter accounts for 10 - 15% of renal excretion. Total clearance is about 110 mL/min and renal clearance is approximately 90 mL/min. Volume of distribution is approximately 20 L.

The biological effect of clodronate disodium is based on its concentration at the site of action, i.e. in bone tissue. Its half-life is dependent on the rate of skeletal turnover. If the bound substance is released from bone tissue on bone breakdown, there is a high local concentration at the site of osteolysis, which has a direct action on the bone-resorbing osteoclasts, their mononuclear precursors and other bone-disintegrating cells.

Toxicology

As a bisphosphonate, clodronate disodium has a high affinity for hydroxyapatite of the bone. This simultaneously explains its low toxicity. The good tolerability and relatively low toxicity of clodronate disodium on parenteral administration with respect to pharmacologically active doses has been confirmed both in acute experiments and in subchronic toxicity tests. On i.v. administration, the doses of 30 mg/kg/day in the dog and 100 mg/kg/day in the rat are still within the tolerated range.

Clodronate disodium exhibits relatively little toxicity either on single oral administration or after daily oral administration for a period of up to 9 months. In the chronic toxicity test in rats, a dose of 200 mg/kg/day is at the limit of tolerability. In dogs, 40 mg/kg/day chronically are within the tolerated range.

On daily oral administration of 500 mg/kg for 6 weeks to rats, signs of renal failure with a clear rise in blood urea nitrogen and initial liver parenchymal reaction with rises of SGOT, SGPT and AP occurred. No significant hematological changes were found in the toxicological investigations.

Acute Toxicity

Acute toxicity (LD50) in mice, rats and guinea pigs was studied after oral, intramuscular (i.m.) a nd intravenous (i.v.) administration.

Species Route LD50 mg/kg
Male Female
Mouse Oral >2000 >2000
i.m. 711* 893
i.p. 722 793
i.v. 238 236
Rat Oral 635 1798
i.p. 399 465
i.v. 65.2 -----
Guinea Pig Oral >2000 >2000
i.m. 316 346

*Range

Subacute Toxicity

Subacute toxicity in rats and dogs was studied after oral, intramuscular (i.m.) and intravenous (i.v.) administration.

Species Route Doses
mg/kg/day
Duration
days (wks)
Observation
Rat Oral 500/300 42(6) All doses well tolerated. No deaths. No hematological disorders. Rise in BUN, slight rise in SGOT and SGPT, and rise in AP in high dose groups.
i.m. 10-20-15 42(6) All doses well tolerated. No deaths. Normal weight gain. Slight fall in hemoglobin in males. Leukopenia in high dose groups. No significant electrolyte changes.
i.v. 100/50/25 30(6)(1) From 5th week onward, animals in high dose groups showed respiratory insufficiency with dyspnea and deterioration in general well-being. Pneumonia demonstrated in autopsy. Dose dependent decrease in body weight and food intake. High dose groups showed increase in prothrombin time and reduced leukocyte count, hemoglobin and hematocrit. High dose groups showed significant rise in BUN and slight increase in SGOT and LDH.
i.v. 750(450)/150/30 28(4) Highest dose was highly toxic. 25/50 animals died, body weight gain was reduced, food consumption decreased along with haematological parameters haemoglobin, erythrocytes, lymphocytes and haematocrit. Increased values for reticulocytes and platelets, plasma glucose, blood urea, plasma ALAT, ASAT, LDH and aP. Histopathology revealed pathological findings in GI tract, kidneys, liver, testicles. At mid dose, reduction in body wgt gain, haemoglobin, erythrocytes, lymphocytes, haematocrit. Increase values for reticulocytes, platelets, activity of ALAT, ASAT, LDH in plasma. Lowest dose caused slight, not significant increase of ALAT and ASAT activity.
Dog Oral 100/50 63(9) All doses well tolerated. No deaths. No drug induced hematological, biochemical or urinary changes.
i.m. 05-10-15 60(10)2 All doses well tolerated. No deaths. No changes in behaviour. Normal body weight development. No drug induced hematological or biochemical changes. Increased excretion of in-organic phosphate, calcium and chloride in males.
i.v. 06-30-15 30(5)3 All doses well tolerated. No deaths. No drug induced hematological or biochemical changes. Increased excretion of inorganic phosphate in all dose groups. Increased calcium excretion in high dose groups.
i.v. 100/45/20 28(4) Highest dose was highly toxic. Mid dose lies at limit of tolerance, producing drug-related clinical changes/biochemical changes in blood parameters. Lowest dose produced no substance-related effects.
1 The substance was administered for 6 weeks, 5 times a week.
2 Administered 6 days/week for 10 weeks.
3 Administered 6 days/week for 5 weeks

Chronic Toxicity

Chronic toxicity in rats and dogs was studied after oral administration.

Species Route Doses
mg/kg/day
Duration
days (wks)
Observation
Rat Oral 200/100 26 (6) All doses well tolerated. No deaths. Slight delay in body weight gain in high dose groups. No drug induced hematological changes. No significant increase in BUN, serum protein, cholesterol, inorganic phosphate or potassium levels. No significant reduction of total lipids, calcium or sodium levels. Slight rise in SGPT and AP.
Oral 300/200/100 26 (6) All doses well tolerated. No deaths. For high dose groups, slight increase in leukocyte count and AP. Significant decrease in packed cell volume neutrophils (female), and serum phosphate.
Oral 400/250/100 52(12) Highest dose was toxic. Trabeculae extension not reversible in high dose group. Leukocytosis was dose dependant and appeared in mid and high dose group and disappeared during recovery period. Liver was affected in dose-dependent manner (increase in S-ALAT and SASAT). No evidence that kidney was affected. Mid dose was at limit of tolerable range. Lowest dose was within tolerated range.
Oral 750(450)/150/30 28(4) Highest dose was highly toxic. 25/50 animals died, body weight gain was reduced, food consumption decreased along with haematological parameters haemoglobin, erythrocytes, lymphocytes and haematocrit. Increased values for reticulocytes and platelets, plasma glucose, blood urea, plasma ALAT, ASAT, LDH and aP. Histopathology revealed pathological findings in GI tract, kidneys, liver, testicles. At mid dose, reduction in body wgt gain, haemoglobin, erythrocytes, lymphocytes, haematocrit. Increase values for reticulocytes, platelets, activity of ALAT, ASAT, LDH in plasma. Lowest dose caused slight, not significant increase of ALAT and ASAT activity.
Dog Oral 40/20 9 All doses well tolerated. No deaths. No drug induced biochemical or urinalysis changes.
Mini Pig Oral 600/300/150 52(12) Highest dose was highly toxic. Changes in stomach and enzymes related to liver. Mid dose was at limit of tolerance ie. produced marginal changes in enzyme levels. Low dose was well tolerated. Only pharmacodynamic changes in bone were observed illustrating intended action of drug. All changes normalized during recovery period.

Teratological and Reproduction Studies

Orally administered clodronate disodium at doses of 100 or 300 mg/kg/day to pregnant rats, or at doses of 200 mg/kg/day to pregnant rabbits, is neither embryotoxic, fetotoxic or has teratogenic effects.

In combined fertility and peri- and post-natal toxicity studies in Wister rats, subcutaneously administered clodronate disodium at a dose of 20 mg/kg/day was shown to have no effect on reproduction. In pregnant rats, clodronate disodium was neither embryotoxic nor fetotoxic. There was no evidence of any teratogenic effect on any of the offspring which ultimately produced an F2 generation without any signs of impaired fertility.

Carcinogenicity

Carcinogenicity studies were performed in rats and mice after daily gavage administration.

Species Route Doses
mg/kg/day
Duration
days (wks)
Observation
Mouse Gavage 45/150/400 80 An 80-week carcinogenicity study in the mouse was performed. Disodium clodronate was administered daily by gavage at doses of 45, 150 & 400 mg/kg. The incidence of tumors in the animals treated with disodium clodronate did not differ significantly from that of the controls and there was no trend for doseresponse relationship in the incidence of neoplastic changes. The data also indicated that mortality in animals treated with sodium clodronate did not differ from that in controls. It was concluded that disodium clodronate was not carcinogenic at the doses administered and does not increase mortality.
Rat Gavage 50/100/200 104 A 104-week carcinogenicity study in the rat was performed. Disodium clodronate was administered daily by gavage at doses of 50, 100, 200 mg/kg. The spectrum of neoplastic changes and their incidence did not differ notably between control group and the test article treated groups. Positive trend towards basal cell tumour of the skin in males. Positive trend towards Ccell carcinoma in thyroid glands and theca-granulosa cell tumour in ovary in females. Frequency did not exceed non-treated control groups. Test article increased trabecular extension (an elongation and increase in the number of columns of calcified cartilage) in femur and sternum bone both in males and females in a dose dependent fashion. The data also indicated that mortality in animals treated with sodium clodronate did not differ from that in controls. It was concluded that disodium clodronate was not carcinogenic at the doses administered and does not increase mortality.

Mutagenicity

In vitro mutagenicity has been evaluated in the following test systems:

  • The Ames Test using salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98 and TA 100 in the presence and absence of a rat liver S9 homogenate.
  • The micronucleus test in bone marrow erythrocytes of NMRI mice.
  • The DNA synthesis test (repair test in human cells) with and without rat liver homogenates.
  • The 5 - Loci mutation test in Schizosaccharomyces pombe in the presence and absence of a metabolic activity system.
  • Mutation test at HPRT locus of V79 Chinese hamster cells (resistance to 6-thioguanine) in presence and absence of a rat liver S9 homogenate.
  • Test for chromosomal abberations by means of metaphase analysis on cultured human lymphocytes in presence and absence of rat liver S9 homogenate.

No mutagenic effect was found with any of the in vitro test systems. In vivo mutagenicity was investigated by means of the micronucleus test using adult Swiss mice. The results of the micronucleus test indicated that clodronate disodium, at the doses used, did not induce the formation of micronuclei in the marrow of Swiss mice and therefore was not mutagenic in the test system.