| Indication |
For treatment of Paget's disease of bone (osteitis deformans). |
| Pharmacodynamics |
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. |
| Volume of distribution |
Not Available |
| Protein binding |
Approximately 90% bound to human serum protein (mainly albumin) at plasma concentrations between 1 and 10 mg/L. |
| Metabolism |
In vitro, tiludronic acid is not metabolized in human liver
microsomes and hepatocytes. There is no evidence that tiludronate is
metabolized in humans. |
| Route of elimination |
The principal route of elimination of tiludronic acid is in the urine. |
| Half life |
Half-life in healthy subjects is 50 hours following administration
of a 400 mg single oral dose. Half-life in pagetic patients is about
150 hours following administration of 400 mg tiludronate a day for 12
days. In patients with renal insufficiency (creatinine clearance between
11 and 18 mL per minute [mL/min]), half-life is 205 hours from plasma
after administration of a single, oral dose equivalent to 400 mg
tiludronate. |
| Clearance |
- renal cl=10 mL/min [IV administration of 20-mg dose]
|
| 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. |
