TILUDRONIC ACID

US Previously Marketed

Details

Stereochemistry	ACHIRAL
Molecular Formula	C7H9ClO6P2S
Molecular Weight	318.608
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(=O)C(SC1=CC=C(Cl)C=C1)P(O)(O)=O

InChI

InChIKey=DKJJVAGXPKPDRL-UHFFFAOYSA-N

InChI=1S/C7H9ClO6P2S/c8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14/h1-4,7H,(H2,9,10,11)(H2,12,13,14)

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020707s006lbl.pdf | https://www.drugbank.ca/drugs/DB01133 | http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/243/skelid-tiludronate-disodium | https://www.ncbi.nlm.nih.gov/pubmed/11249559

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).

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ATP 10 Target ID: CHEMBL2366048 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21111853 \| https://www.drugbank.ca/drugs/DB01133 \| https://www.ncbi.nlm.nih.gov/pubmed/20722616	Inhibitor 8297
Osteoclasts 3 Target ID: CHEMBL612548 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8573421 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020707s006lbl.pdf	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Paget's disease 16 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020707s006lbl.pdf https://www.ncbi.nlm.nih.gov/pubmed/11249559	Primary		Approved 8429	SKELID Approved Use SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans). Launch Date 1997

C_max

Value	Dose	Analyte	Population
1.1 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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

Value	Dose	Analyte	Population
10.3 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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

T_1/2

Value	Dose	Analyte	Population
78 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/8911885/	healthy, 18 - 45 years n = 10 Health Status: healthy Age Group: 18 - 45 years Sex: M Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/8911885/	Sources: https://pubmed.ncbi.nlm.nih.gov/8911885/
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: https://pubmed.ncbi.nlm.nih.gov/8427515/	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: https://pubmed.ncbi.nlm.nih.gov/8427515/	Other AEs: Gastrointestinal disturbance... Other AEs: Gastrointestinal disturbance (3 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/8427515/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/	DLT: Gastrointestinal symptom NOS... Dose limiting toxicities: Gastrointestinal symptom NOS (31%) Sources: https://pubmed.ncbi.nlm.nih.gov/9307742/

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/8427515/	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: https://pubmed.ncbi.nlm.nih.gov/8427515/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/
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: https://pubmed.ncbi.nlm.nih.gov/9307742/	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: https://pubmed.ncbi.nlm.nih.gov/9307742/

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY578611	https://www.001chemical.com/chem/89987-06-4
3B Scientific (Wuhan) Corp	3B2-1368	http://www.3bsc.com/index/pro_info.php?id=55084
AHH Chemical co.,ltd	MT-59523	http://www.ahhchemical.com/product/MT-59523.html
Alfa Chemistry	ALP89987064	https://reagents.alfa-chemistry.com/product/tiludronate-disodium-salt-hydrate-cas-89987-06-4-free-acid-402.html
Ambinter	Amb22269245	http://www.ambinter.com/reference/22269245
BLD Pharm	BD154148	http://www.bldpharm.com/products/89987-06-4.html
ChemMol	49422201	http://www.chemmol.com/chemmol/49422201.html
ChemMol	99162429	http://www.chemmol.com/chemmol/99162429.html
Finetech	FT-0630969	http://www.finetechnology-ind.com/prod/detail/pub/89987-06-4.html
Glentham Life Sciences	GP4498	http://www.glentham.com/products/product/GP4498/
Molcore	MC578611	https://www.molcore.com/product/89987-06-4
OChem	21129	http://www.ocheminc.com/index.php?act=psearch&pid=987T064
Smolecule	S560068	https://www.smolecule.com/products/s560068
THE BioTek	bt-363849	https://www.thebiotek.com/product/others/bt-363849
iChemical	EBD52449	http://www.ichemical.com/chemicals/cas-89987-06-4

PubMed

Title	Date	PubMed
Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget's disease of bone.	1988	3073800
A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders.	1995 Aug	8554921
Human pharmacokinetics of tiludronate.	1995 Nov	8573422
Consensus statement on the modern therapy of Paget's disease of bone from a Western Osteoporosis Alliance symposium. Biannual Foothills Meeting on Osteoporosis, Calgary, Alberta, Canada, September 9-10, 2000.	2001 Apr	11354395
Current management strategies for hypercalcemia.	2003	15966562
New insights into the molecular mechanisms of action of bisphosphonates.	2003	14529538
Bisphosphonate resistance in Paget's disease of bone.	2003 Aug	12905487
[Possible mechanism of the specific action of bisphosphonates on osteoclasts].	2003 Feb	12638209
Medical treatment of vertebral osteoporosis.	2003 Oct	13680313
Management of Paget's disease of bone.	2004 Aug	15187244
Effect of bisphosphonate treatment in patients with Paget's disease of the skull.	2004 Jan	12923287
Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.	2004 Nov 1	15477866
In vitro toxicity of bisphosphonates on human neuroblastoma cell lines.	2004 Sep	15494642
Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone.	2005 Apr	15765177
[Paget's disease and its therapeutic management].	2005 Apr 23	15962504
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.	2005 May 31	15922088
Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women.	2006	18046915
Gateways to clinical trials.	2006 Apr	16810345
Medical management of Paget's disease of bone: indications for treatment and review of current therapies.	2006 Dec	17229018
Biochemical response to bisphosphonate therapy in pagetic patients with skull involvement.	2006 Jul	16868670
Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.	2006 Mar	16673205
Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy.	2007 Mar-Apr	17543143
Pharmacological effects of tiludronate in horses after long-term immobilization.	2007 Sep	17604709
Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1.	2008 Apr	18307502
Treatment of Paget's disease of bone: a survey of clinical practice in Australia.	2008 Jun	18353737
Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages.	2010	20722616
Prolonged unilateral disuse osteopenia 14 years post external fixator removal: a case history and critical review.	2010	20445732
Bisphosphonates and risk of atrial fibrillation: a meta-analysis.	2010	20170505
Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors.	2013 Nov 1	24071448

Patents

Sample Use Guides

In Vivo Use Guide

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

TILUDRONIC ACID

Official Name

English

TILUDRONATE [VANDF]

Common Name

English

SR-41319

Code

English

Tiludronic acid [WHO-DD]

Common Name

English

TILUDRONATE

Common Name

English

SR 41319

Code

English

TILUDRONIC ACID [MART.]

Common Name

English

TILUDRONIC ACID [MI]

Common Name

English

tiludronic acid [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C67439