ZOLEDRONATE DISODIUM ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C5H8N2O7P2.2Na
Molecular Weight	316.0533
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of ZOLEDRONATE DISODIUM ANHYDROUS

Structure Search

SMILES

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

InChI

InChIKey=OPQQEYHAVUNQNA-UHFFFAOYSA-L

InChI=1S/C5H10N2O7P2.2Na/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);;/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
Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment.	2001 Apr	11346863
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
Unmet needs in metastatic bone disease and its complications: is progress possible?	2001 Apr	11346858
New advances in the biology and treatment of myeloma bone disease.	2001 Apr	11309704
Analysis of skeletal-related events in breast cancer and response to therapy.	2001 Aug	11544572
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.	2001 Jan 15	11208851
The effects of MMP inhibitors on human salivary MMP activity and caries progression in rats.	2001 Jun	11499510
[Bone metastasis. Can a new bisphosphonate offer control?].	2001 Mar 1	11288542
Advances in the biology and treatment of myeloma bone disease.	2001 Nov 15	11757204
A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease.	2001 Oct	11680835
U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid.	2002	12401901
Development of bisphosphonates.	2002	11879557
Direct effects of bisphosphonates on breast cancer cells.	2002	11879555
Advances in the biology and treatment of myeloma bone disease.	2002 Dec	12520479
Monosodium [1-hydroxy-2-(1H-imidazol-3-ium-4-yl)ethane-1,1-diyl]bis(phosphonate) tetrahydrate (monosodium isozoledronate).	2002 Dec	12466610
Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity.	2002 Feb	11841428
The effects of local administration of Zoledronate solution on the tooth movement and periodontal ligament.	2002 Jul	12411180
New drugs 2002, part III.	2002 Jul	12352871
Zoledronate once-yearly increases bone mineral density--implications for osteoporosis.	2002 Jul	12083999
Novel approaches to the management of bone metastases in patients with breast cancer.	2002 Jun	12138408
Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts.	2002 Jun	12109626
Bisphosphonates and osteoporosis.	2002 Jun 27	12087149
The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage.	2002 Mar	11869084
Treatment of malignant hypercalcaemia.	2002 May	11996631
Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases.	2002 Nov	12412821
Severe increase in creatinine with hypocalcaemia in thalidomide-treated myeloma patients receiving zoledronic acid infusions.	2002 Nov	12406106
Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.	2002 Nov	12406088
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: new preparation. Just a me-too: no advance in hypercalcemia of malignancy.	2002 Oct	12378744
Intravenous zoledronic acid in postmenopausal women with low bone mineral density.	2002 Oct	12356057
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
Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.	2002 Sep	12183663
[Bisphosphonates in bone metastases. Fewer fractures, less pain].	2002 Sep 26	12422697

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 ANHYDROUS

Common Name

English

PHOSPHONIC ACID, P,P'-(1-HYDROXY-2-(1H-IMIDAZOL-1-YL)ETHYLIDENE)BIS-, SODIUM SALT (1:2)

Common Name

English

Code System Code Type Description

PUBCHEM

3684056