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Details

Stereochemistry ACHIRAL
Molecular Formula 2C7H7ClO6P2S.4Na.H2O
Molecular Weight 743.159
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TILUDRONATE DISODIUM HEMIHYDRATE

SMILES

O.[Na+].[Na+].[Na+].[Na+].OP([O-])(=O)C(SC1=CC=C(Cl)C=C1)P(O)([O-])=O.OP([O-])(=O)C(SC2=CC=C(Cl)C=C2)P(O)([O-])=O

InChI

InChIKey=KDVKAYPVWJFARG-UHFFFAOYSA-J
InChI=1S/2C7H9ClO6P2S.4Na.H2O/c2*8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14;;;;;/h2*1-4,7H,(H2,9,10,11)(H2,12,13,14);;;;;1H2/q;;4*+1;/p-4

HIDE SMILES / InChI
Tiludronic acid is a bisphosphonate characterized by a (4-chlorophenylthio) group on the carbon atom of the basic P-C-P structure common to all bisphosphonates. 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. Tiludronic acid is marketed under the tradename Skelid. 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. SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
SKELID

Approved Use

SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Launch Date

1997
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.1 mg/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
2.3 mg/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
4.7 mg/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
7.8 mg/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
10.3 mg × h/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
25 mg × h/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
46.8 mg × h/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
80 mg × h/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
78 h
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
65.7 h
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
72 h
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
800 mg 1 times / day steady, oral
Studied dose
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
healthy, 18 - 45 years
n = 10
Health Status: healthy
Age Group: 18 - 45 years
Sex: M
Population Size: 10
Sources:
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Other AEs: Gastrointestinal disturbance...
Other AEs:
Gastrointestinal disturbance (3 patients)
Sources:
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
DLT: Gastrointestinal symptom NOS...
Other AEs: Nausea, Diarrhoea...
Dose limiting toxicities:
Gastrointestinal symptom NOS (75%)
Other AEs:
Nausea (7 patients)
Diarrhoea (7 patients)
Arthralgia (2 patients)
Dyspepsia (5 patients)
Skeletal pain (3 patients)
Vomiting (6 patients)
Sources:
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
DLT: Gastrointestinal symptom NOS...
Dose limiting toxicities:
Gastrointestinal symptom NOS (31%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Gastrointestinal disturbance 3 patients
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Arthralgia 2 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Skeletal pain 3 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Dyspepsia 5 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Vomiting 6 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Diarrhoea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Nausea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 75%
DLT, Disc. AE
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 31%
DLT, Disc. AE
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
PubMed

PubMed

TitleDatePubMed
Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget's disease of bone.
1988
A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders.
1995 Aug
Human pharmacokinetics of tiludronate.
1995 Nov
Effect of surgical menopause and Paget's disease of bone on the isomerization of type I collagen carboxyterminal telopeptide: evolution after antiresorptive therapy.
2002
New insights into the molecular mechanisms of action of bisphosphonates.
2003
Drugs in development: bisphosphonates and metalloproteinase inhibitors.
2003
Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival.
2003 Jul 7
Management of Paget's disease of bone.
2004 Aug
Effect of bisphosphonate treatment in patients with Paget's disease of the skull.
2004 Jan
Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment.
2004 Jul
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women.
2006
-511 C/T IL1B gene polymorphism is associated to resistance to bisphosphonates treatment in Paget disease of bone.
2006 Apr
Medical management of Paget's disease of bone: indications for treatment and review of current therapies.
2006 Dec
Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187.
2006 Jul-Aug
Management of age-related osteoporosis and prevention of associated fractures.
2006 Sep
Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column.
2007 Mar
Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy.
2007 Mar-Apr
Use of zoledronic acid in the treatment of Paget's disease.
2007 Oct
Pharmacological effects of tiludronate in horses after long-term immobilization.
2007 Sep
Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations.
2008
Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1.
2008 Apr
Treatment of Paget's disease of bone: a survey of clinical practice in Australia.
2008 Jun
Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: a review of analytical methods.
2008 Nov 4
Paget disease of bone: therapeutic options.
2008 Oct
Paget's disease 2: exploring diagnosis, management and support strategies.
2009 Feb 24-Mar 2
Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.
2009 Sep 21
Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages.
2010
Bisphosphonates and risk of atrial fibrillation: a meta-analysis.
2010
Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial.
2010 Jul
Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis.
2010 Jul 21
Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series.
2010 May 31
Bisphosphonate protonation states, conformations, and dynamics on bone mineral probed by solid-state NMR without isotope enrichment.
2010 Sep
Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors.
2013 Nov 1
Patents

Sample Use Guides

A single 400-mg daily oral dose of SKELID (Tiludronic acid), taken with 6 to 8 ounces of plain water only, should be administered for a period of 3 months. Beverages other than plain water (including mineral water), food (see below), and some medications. Patients should not lie down for at least 30 minutes after taking this medication. SKELID should not be taken within 2 hours of food.
Route of Administration: Oral
In Vitro Use Guide
The ability of tiludronate to inhibit proton transport was 5-fold higher in kidney-derived chicken vesicles (IC50 = 1.1 mM) and 10,000-fold higher in vesicles derived from chicken osteoclasts (IC50 = 466 nM). Tiludronate also potently inhibited proton transport in yeast microsomal preparations (IC50 = 3.5 uM) and inhibited the activity of purified yeast V-ATPase.
Name Type Language
TILUDRONATE DISODIUM HEMIHYDRATE
Common Name English
TILUDRONIC ACID DISODIUM SALT HEMIHYDRATE [MI]
Common Name English
P,P'-(((4-CHLOROPHENYL)THIO)METHYLENE)BISPHOSPHONIC ACID, DISODIUM HEMIHYDRATE
Systematic Name English
PHOSPHONIC ACID, (((4-CHLOROPHENYL)THIO)METHYLENE)BIS-, DISODIUM SALT, HYDRATE (2:1)
Systematic Name English
Code System Code Type Description
CAS
155453-10-4
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
PUBCHEM
72941702
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
MERCK INDEX
m10868
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
FDA UNII
39SMX0W5WK
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY