Basic Profile / Key Facts
Drug Category
- Antihypocalcemic Agents
- Osteoporosis Prophylactic
Dosage Forms
- Tablets for oral administration containing 240 mg tiludronate disodium
Indications
For treatment of Paget's disease of bone (osteitis deformans).
Pharmacology
Tiludronate is a first generation (non-nitrogenous) bisphosphonate in the same family as etidronate and clodronate. Tiludronate affects calcium metabolism and inhibits bone resorption and soft tissue calcification. Of the tiludronate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface.
Mechanism of Action
The bisphosphonate group binds strongly to the bone mineral, hydroxyapatite. This explains the specific pharmacological action of these compounds on mineralized tissues, especially bone. In vitro studies indicate that tiludronate acts primarily on bone through a mechanism that involves inhibition of osteoclastic activity with a probable reduction in the enzymatic and transport processes that lead to resorption of the mineralized matrix. Bone resorption occurs following recruitment, activation, and polarization of osteoclasts. Tiludronate appears to inhibit osteoclasts by at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to detachment of osteoclasts from the bone surface and the inhibition of the osteoclastic proton pump.
Absorption
The mean oral bioavailability in healthy male subjects is 6% after an oral dose equivalent to 400 mg tiludronic acid administered after an overnight fast and 4 hours before a standard breakfast. In single-dose studies, bioavailability was reduced by 90% when an oral dose equivalent to 400 mg tiludronic acid was administered with, or 2 hours after, a standard breakfast compared to the same dose administered after an overnight fast and 4 hours before a standard breakfast.
Toxicity
Based on the known action of tiludronate, hypocalcemia is a potential consequence of overdose. In one patient with hypercalcemia of malignancy, intravenous administration of high doses (800 mg/day total dose, 6 mg/kg/day for 2 days) was associated with acute renal failure and death.
Biotrnasformation / Drug Metabolism
In vitro, tiludronic acid is not metabolized in human liver microsomes and hepatocytes. There is no evidence that tiludronate is metabolized in humans.
Contraindications
SKELID is contraindicated in individuals with known hypersensitivity to any component of this product.
Drug Interactions
The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same
time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may
decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is
increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The
pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro
studies show that tiludronate does not displace warfarin from its binding site on protein.
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