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Pharmacological particulars
Pharmacotherapeutic group: Bisphosphonates. ATCvet code: QM05BA05
Pharmacodynamic properties
The pharmacodynamic effects of tiludronic acid have been investigated in-vitro, in laboratory animals and in the horse.
Tiludronic acid exerts its inhibitory effect on bone resorption by blocking some of the osteoclast metabolic pathways (production of non-hydrolysable, cytotoxic, ATP-analogue metabolites, inhibition of the organisation of the cytoskeleton required for the activation of the osteoclast and inhibition of the osteoclastic proton pumps). Tiludronic acid helps in regulating bone remodelling in every situation where excessive bone resorption (i.e. increased osteoclastic activity) is occurring. Osteolysis is a painful process. In the horse, bone spavin is a condition where osteolytic lesions develop in tarsal bones, which contributes to the clinical symptoms. In laboratory animals the regulatory effect on bone remodelling is not accompanied by negative effects on the formation and mineralisation of bone at doses sufficient to significantly inhibit bone resorption.
Pharmocodynamic data in horses free of lameness have shown that, after intravenous administration at the dose 1 mg/kg, tiludronic acid produces immediate inhibitory effects on bone resorption, as shown by the sharp decrease of a serum marker of bone resorption (CTX-1) 12 to 24 hours after dosing. Tiludronic acid was also shown to prevent the loss of bone density after a period of immobilisation by casting.
At therapeutic doses, bone formation was not impaired as shown by the absence of significant changes in the blood concentrations of a marker of bone formation (bone alkaline phosphatase).
Tiludronic acid has also been shown to have anti-arthritic properties in a polyarthritis model in the rat. In vitro studies have revealed that the product has inhibitory effects on the secretion of enzymes degrading the cartilaginous matrix produced by the chondrocytes and the synovial cells.
Pharmacokinetic particulars
The pharmacokinetic profile of tiludronic acid in plasma after intravenous administration by infusion over 30 minutes in the horse at a dose of 1 mg/kg/day is characterised by a rapid decrease in plasma concentrations. Cmax is about 8 + 2 mg/l , plasma t ½ is short, about 37 + 20 hours, and total clearance is about 0.03+ 0.01 l/h/kg. There is no plasma accumulation of tiludronic acid when infusions are repeated 3 times at 14-day intervals. The pharmacokinetic profile of tiludronic acid is dose- proportional and time-independent.
Binding to plasma proteins is of about 80% - 85%.
Tiludronic acid is rapidly cleared from blood and stored in the bone where it preferentially binds to the active remodelling sites, by binding to hydroxyapatite crystals. The bound quantity corresponds to 30 to 50% of the total administered dose. The distribution of tiludronic acid in the bone is not uniform. Binding is greater in cancellous bone than in cortical bone.
The distribution of the drug in all other body tissues is limited. It is not metabolised. Tiludronic acid is eliminated mainly via the urine, in unchanged form.