ZOLEDRONATE DISODIUM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C5H8N2O7P2.2Na.4H2O
Molecular Weight	388.1144
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.O.O.O.[Na+].[Na+].OC(CN1C=CN=C1)(P(O)([O-])=O)P(O)([O-])=O

InChI

InChIKey=IEJZOPBVBXAOBH-UHFFFAOYSA-L

InChI=1S/C5H10N2O7P2.2Na.4H2O/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7;;;;;;/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14);;;4*1H2/q;2*+1;;;;/p-2

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21386lbl.pdf

Zoledronic acid (Reclast, Aclasta, Zometa) is an intravenous, highly potent amino-bisphosphonate approved worldwide, including in the USA, EU and Japan for use in patients with primary or secondary osteoporosis or low bone mass (approved indications vary between countries). Its high affinity to and long half-life in bone, and long duration of action allow for once-yearly administration, which has the potential to improve adherence to therapy. Zoledronic acid once yearly for up to 3 years improved bone mineral density (BMD) at several skeletal sites, reduced fracture risk and bone turnover, and/or preserved bone structure and mass relative to placebo in clinical studies in patients with primary or secondary osteoporosis. While additional benefits were seen when treatment was continued for up to 6 years, as evidenced by a reduced risk of vertebral fractures and higher BMD relative to 3 years’ therapy, there was the minimal advantage of treatment beyond 6 years. Therefore, in patients with low fracture risk, treatment discontinuation should be considered after approximately 5 years’ therapy. Zoledronic acid administered annually or once in 2 years was also effective in preventing bone loss in patients with low bone mass. Zoledronic acid was generally well tolerated, with the most common adverse events (AEs) being transient, mild-to-moderate post-infusion symptoms, which decreased with subsequent infusions.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Farnesyl diphosphate synthase 28 Target ID: CHEMBL1782 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22390415	Inhibitor 8297	4.1 nM [IC50]
Geranylgeranyl pyrophosphate synthetase 18 Target ID: CHEMBL4769 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17535895	Inhibitor 8297	97.0 µM [IC50]
Carbonic anhydrase XIV 22 Target ID: CHEMBL3510 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24813742	Inhibitor 8297	92.0 nM [IC50]
Carbonic anhydrase II 88 Target ID: CHEMBL205 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24650641	Inhibitor 8297	62.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hypercalcemia 21 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21386lbl.pdf	Primary	Approved 8429	Zometa Approved Use INDICATIONS AND USAGE Hypercalcemia of Malignancy. Zometa® (zoledronic acid for injection) is indicated for the treatment of hypercalcemia of malignancy. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated dequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established. Multiple Myeloma and Bone Metastases of Solid Tumors. Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy Launch Date 2001
Disuse osteoporosis 9 Sources: https://clinicaltrials.gov/ct2/show/NCT02042872	Primary	Approved 8429	Zometa Approved Use INDICATIONS AND USAGE Hypercalcemia of Malignancy. Zometa® (zoledronic acid for injection) is indicated for the treatment of hypercalcemia of malignancy. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated dequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established. Multiple Myeloma and Bone Metastases of Solid Tumors. Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy Launch Date 2001
Prostate cancer with bone metastasis 9 Sources: https://clinicaltrials.gov/ct2/show/NCT00241111	Primary	Approved 8429	Zometa Approved Use INDICATIONS AND USAGE Hypercalcemia of Malignancy. Zometa® (zoledronic acid for injection) is indicated for the treatment of hypercalcemia of malignancy. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated dequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established. Multiple Myeloma and Bone Metastases of Solid Tumors. Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy Launch Date 2001
Renal osteodystrophy 11 Sources: https://clinicaltrials.gov/ct2/show/NCT01675089	Primary	Approved 8429	Zometa Approved Use INDICATIONS AND USAGE Hypercalcemia of Malignancy. Zometa® (zoledronic acid for injection) is indicated for the treatment of hypercalcemia of malignancy. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated dequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established. Multiple Myeloma and Bone Metastases of Solid Tumors. Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy Launch Date 2001
Postmenopausal osteoporosis 59 Sources: https://clinicaltrials.gov/ct2/show/NCT02499237	Primary	Approved 8429	Zometa Approved Use INDICATIONS AND USAGE Hypercalcemia of Malignancy. Zometa® (zoledronic acid for injection) is indicated for the treatment of hypercalcemia of malignancy. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated dequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established. Multiple Myeloma and Bone Metastases of Solid Tumors. Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy Launch Date 2001

C_max

Value	Dose	Co-administered	Analyte	Population
264 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21563999	4 mg single, intravenous dose: 4 mg route of administration: Intravenous experiment type: SINGLE co-administered:		ZOLEDRONIC ACID plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
420 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21563999	4 mg single, intravenous dose: 4 mg route of administration: Intravenous experiment type: SINGLE co-administered:		ZOLEDRONIC ACID plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
39 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21563999	4 mg single, intravenous dose: 4 mg route of administration: Intravenous experiment type: SINGLE co-administered:		ZOLEDRONIC ACID plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
16 mg 1 times / 4 weeks multiple, intravenous Highest studied dose Dose: 16 mg, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 16 mg, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/12412821	unhealthy, 40-79 years n = 12 Health Status: unhealthy Condition: cancer Age Group: 40-79 years Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/12412821	Sources: https://pubmed.ncbi.nlm.nih.gov/12412821
16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	Other AEs: Skeletal pain, Fever... Other AEs: Skeletal pain (30%) Fever (20%) Anorexia (20%) Diarrhea (20%) Constipation (10%) Nausea (20%) Myalgia (20%) Arthralgia (10%) Anemia (30%) Rigors (20%) Coughing (20%) Leg edema (10%) Urinary tract infection (10%) Fatigue (40%) Sources: https://pubmed.ncbi.nlm.nih.gov/11148571

AEs

AE	Significance	Dose	Population
Arthralgia	10%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Constipation	10%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Leg edema	10%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Urinary tract infection	10%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Anorexia	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Coughing	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Diarrhea	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Fever	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Myalgia	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Nausea	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Rigors	20%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Anemia	30%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Skeletal pain	30%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571
Fatigue	40%	16 mg single, intravenous Highest studied dose Dose: 16 mg Route: intravenous Route: single Dose: 16 mg Sources: https://pubmed.ncbi.nlm.nih.gov/11148571	unhealthy, 54 years (range: 34–73 years) n = 10 Health Status: unhealthy Condition: cancer Age Group: 54 years (range: 34–73 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/11148571

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP450 25	CYP 270

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP450 41	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021817s000_PharmR_P1.pdf#page=50 Page: 50.0	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682380/	no

PubMed

Title	Date	PubMed
Zoledronic acid: an evolving role in the treatment of cancer patients with bone disease.	2001 Apr	11346864
Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment.	2001 Apr	11346863
Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials.	2001 Apr	11346862
Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program.	2001 Apr	11346861
The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases.	2001 Apr	11346860
[Bisphosphonates in the treatment of breast carcinoma].	2001 Aug	11926150
Adjuvant bisphosphonate therapy: the future.	2001 Aug	11544582
[Tumor-induced hypercalcemia. Review of bisphosphonate treatment].	2001 Jul	11508158
[Bone metastasis. Can a new bisphosphonate offer control?].	2001 Mar 1	11288542
Bisphosphonate treatment inhibits the growth of prostate cancer cells.	2001 Mar 15	11289137
Early detection of bone metastases in a murine model using fluorescent human breast cancer cells: application to the use of the bisphosphonate zoledronic acid in the treatment of osteolytic lesions.	2001 Nov	11697798
Conventional treatment of hypercalcemia of malignancy.	2001 Nov 15	11757206
FDA grants priority review for ZOMETA.	2001 Oct	12113096
A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease.	2001 Oct	11680835
From the Food and Drug Administration.	2001 Oct 3	11585463
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.	2001 Sep-Oct	11693896
Advances in the biology and treatment of myeloma bone disease.	2002 Dec	12520479
Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain.	2002 Dec	12467993
The role of osteoclastic activity in prostate cancer skeletal metastases.	2002 Feb	12532187
Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity.	2002 Feb	11841428
New drugs 2002, part III.	2002 Jul	12352871
Bisphosphonates for cancer patients: why, how, and when?	2002 Jul	12136223
Zoledronate once-yearly increases bone mineral density--implications for osteoporosis.	2002 Jul	12083999
Treatment of malignant hypercalcaemia.	2002 May	11996631
The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells.	2002 May 6	11986784
Development and validation of a highly sensitive RIA for zoledronic acid, a new potent heterocyclic bisphosphonate, in human serum, plasma and urine.	2002 Nov 7	12408879
The use of bisphosphonates in patients with breast cancer.	2002 Nov-Dec	12514566
Zoledronic acid improves the mechanical properties of normal and healing bone.	2002 Nov-Dec	12446169
Zoledronic acid.	2002 Nov-Dec	12434471
Gateways to clinical trials.	2002 Oct	12500432
Zoledronic acid: new preparation. Just a me-too: no advance in hypercalcemia of malignancy.	2002 Oct	12378744
Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model.	2002 Oct 1	12359769
A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.	2002 Oct 2	12359855
American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.	2002 Sep 1	12202673

Patents

Sample Use Guides

In Vivo Use Guide

The maximum recommended dose of Zometa in hypercalcemia of malignancy is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes.

Route of Administration: Intravenous

In Vitro Use Guide

For the transfection of the T24 human bladder cancer cells, pCMV6 empty vector (OriGene, Rockville, MD, USA) and pCMV6 TAp73 vector were transfected into cells using Lipofectamine™ 2000 (Invitrogen Life Technologies). After 6 h, the medium was refreshed and cultured for 48 h. Then the cells were treated with ZA (200 μM).

Name

Type

Language

ZOLEDRONATE DISODIUM

Official Name

English

ZOLEDRONATE DISODIUM [USAN]

Common Name

English

ZOLEDRONATE DISODIUM TETRAHYDRATE

Common Name

English

ZOLEDRONIC ACID DISODIUM SALT TETRAHYDRATE [MI]

Common Name

English

ZOLEDRONATE DISODIUM [MART.]

Common Name

English

CGP 42446A

Code

English

Zoledronate disodium [WHO-DD]

Common Name

English

ZOLEDRONIC ACID DISODIUM SALT TETRAHYDRATE

Common Name

English

Disodium dihydrogen (1-hydroxy-2-imidazol-1-ylethylidene)diphosphonate, tetrahydrate

Systematic Name

English

ZOLEDRONATE DISODIUM HYDRATE

Common Name

English

PHOSPHONIC ACID, (1-HYDROXY-2-(1H-IMIDAZOL-1-YL)ETHYLIDENE)BIS-, DISODIUM SALT TETRAHYDRATE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C67439