Tiludronic acid

In vitro studies indicate that tiludronate disodium 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 disodium appears to inhibit osteoclasts through 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.

Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget’s disease range from no symptoms to severe bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

In pagetic patients treated with tiludronic acid 400 mg/day for 3 months, changes in urinary hydroxyproline, a biochemical marker of bone resorption, and in serum alkaline phosphatase, a marker of bone formation, indicate a reduction toward normal in the rate of bone turnover. In addition, reduced numbers of osteoclasts by histomorphometric analysis and radiological improvement of lytic lesions indicate that tiludronic acid can suppress the pagetic disease process.

Absorption

Relative to an intravenous (IV) reference dose, the mean oral bioavailability of tiludronate disodium in healthy male subjects was 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. However, in clinical studies, efficacy was seen when tiludronic acid was dosed at least 2 hours before or after meals.

After administration of a single dose equivalent to 400 mg tiludronic acid to healthy male subjects, tiludronic acid was rapidly absorbed with peak plasma concentrations of approximately 3 mg/L occurring within 2 hours. In pagetic patients, after repeated administration of doses equivalent to 400 mg/day tiludronic acid (2 hours before or 2 hours after a meal) for durations of 12 days to 12 weeks, average plasma concentrations of tiludronic acid occurring between 1 and 2 hours after dosing ranged between 1 and 4.6 mg/L.

Distribution

Animal pharmacology studies in rats demonstrate that tiludronic acid is widely distributed to bone and soft tissues. Over a period of days, loss of drug occurs from most tissues with the exception of bone and cartilage. Tiludronate is then slowly released from bone with a half-life in rats of 30 days or longer depending on the status of bone turnover.

After oral administration of doses equivalent to 400 mg/day tiludronic acid to nonpagetic patients with osteoarthrosis, the steady state in bone was not reached after 30 days of dosing. At plasma concentrations between 1 and 10 mg/L, tiludronic acid was approximately 90% bound to human serum protein (mainly albumin).

Metabolism

In laboratory animals, tiludronic acid undergoes little if any metabolism. In vitro, tiludronic acid is not metabolized in human liver microsomes and hepatocytes.

Elimination

The principal route of elimination of tiludronic acid is in the urine. After IV administration to healthy volunteers, approximately 60% of the dose was excreted in the urine as tiludronic acid within 13 days. Renal clearance is dose independent and is approximately 10 mL/min in healthy subjects. In pagetic patients treated with doses equivalent to 400 mg/day tiludronic acid for 12 days, the mean apparent plasma elimination half-life was approximately 150 hours. The elimination rate from human bone is unknown.

Special Populations

Geriatric

No dosage adjustment in elderly patients is necessary. Plasma concentrations of tiludronic acid were higher in elderly pagetic patients (≥65 years of age); however, this difference was not clinically significant.

Pediatric

Tiludronic acid pharmacokinetics have not been investigated in subjects under the age of 18 years.

Gender

There were no clinically significant differences in plasma concentrations after repeated administration of tiludronate disodium to male and female pagetic patients.

Race

Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency

Tiludronic acid is not recommended for patients with severe renal failure (creatinine clearance <30 mL/min) due to lack of clinical experience. After a single oral dose equivalent to 400 mg tiludronic acid, subjects with creatinine clearance between 11 and 18 mL/min had C_max values (approximately 3 mg/L) in the range of healthy volunteers. However, the plasma elimination half-life was approximately 205 hours, which is longer than that observed in pagetic patients after repeated doses (150 hours) and healthy subjects after single doses (50 hours). These values were obtained in a cross-study comparison between healthy volunteers and pagetic patients.

Hepatic Insufficiency

No dosage adjustment is needed. Since tiludronate undergoes little or no metabolism, no studies were conducted in subjects with hepatic insufficiency.

Drug-Drug Interactions

The bioavailability of tiludronic acid is decreased 80% by calcium, when calcium and tiludronic acid are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before tiludronic acid. Aspirin may decrease bioavailability of tiludronic acid by up to 50% when taken 2 hours after tiludronic acid. The bioavailability of tiludronic acid is increased 2-4 fold by indomethacin and is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by tiludronic acid coadministration. In vitro studies show that tiludronate disodium does not displace warfarin from its binding site on protein.

Summary of Pharmacokinetic Parameters in the Normal Population:

^* Bioavailability was reduced by 90% when this single oral dose of 400 mg was administered with, or 2 hours after, a standard breakfast.