IFOSFAMIDE

Details

Stereochemistry	RACEMIC
Molecular Formula	C7H15Cl2N2O2P
Molecular Weight	261.086
Optical Activity	( + / - )
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ClCCNP1(=O)OCCCN1CCCl

InChI

InChIKey=HOMGKSMUEGBAAB-UHFFFAOYSA-N

InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)

HIDE SMILES / InChI

Description
Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=17464949https://www.ncbi.nlm.nih.gov/pubmed/27413637 | https://www.ncbi.nlm.nih.gov/pubmed/17786181 | https://pubchem.ncbi.nlm.nih.gov/compound/Glufosfamide

Glufosamide (glucosylifosfamide mustars) consists of iphosphoramide mustard conjugated to glucose, and is an alkylating agent (affecting the ability of the cancer cell to multiply by causing breakage of the DNA strands). Glufosamide is considered a targeted chemotherapy with fewer side effects than alternative chemotherapies. Its specific mode of action on normal and pathological cells is still under investigation. Glufosamide was studied for use in several cancers, like pancreatic and prostate cancer, and head and neck squamous cell carcinoma. Multipe clinical trials have been completed or are still ongoing. Most promising results were found when glufosamide was used in combination treatments, rather than alone.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019763s019lbl.pdf	Crosslinking Agent 81

Conditions

Condition	Modality	Targets	Highest Phase	Product
Germ cell testicular cancer 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019763s019lbl.pdf	Primary		Approved 8429	IFEX Approved Use Ifosfamide injection, used in combination with certain other approved antineoplastic agents, is indicated for third line chemotherapy of germ cell testicular cancer. It should be used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna. Launch Date 1988

C_max

Value	Dose	Co-administered	Analyte	Population
200 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, oral dose: 1.5 g/m² route of administration: Oral experiment type: SINGLE co-administered:		IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
203 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, intravenous dose: 1.5 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:		IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
1360 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, oral dose: 1.5 g/m² route of administration: Oral experiment type: SINGLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1520 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, intravenous dose: 1.5 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7.54 mM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8339288	3 g/m² 1 times / day multiple, intravenous dose: 3 g/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, oral dose: 1.5 g/m² route of administration: Oral experiment type: SINGLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/1795004	1.5 g/m² single, intravenous dose: 1.5 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.12 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8339288	3 g/m² 1 times / day multiple, intravenous dose: 3 g/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	IFOSFAMIDE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
100% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf			IFOSFAMIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
18 g/m2 1 times / day multiple, intravenous (total) MTD Dose: 18 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 18 g/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090	unhealthy, 45 n = 6 Health Status: unhealthy Condition: Sarcoma Age Group: 45 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090	DLT: Neutropenia, Infection... Dose limiting toxicities: Neutropenia (grade 4, 83.3%) Infection (severe, 33.3%) Thrombocytopenia (grade 4, 66.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090
2.25 g/m2 1 times / day multiple, intravenous MTD Dose: 2.25 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 2.25 g/m2, 1 times / day Co-administed with:: doxorubicin, i.v(45 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	unhealthy, 45 n = 3 Health Status: unhealthy Condition: Breast cancer Age Group: 45 Sex: F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	DLT: Neutropenia, Febrile neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 66.7%) Febrile neutropenia (grade 5, 33.3%) Thrombocytopenia (grade 4, 66.7%) Anemia (grade 4, 66.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6
1.2 g/m2 1 times / day multiple, intravenous Recommended Dose: 1.2 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 1.2 g/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Testicular cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1	Disc. AE: Nephrotoxicity, Renal failure... AEs leading to discontinuation/dose reduction: Nephrotoxicity (severe) Renal failure (severe) Cystitis hemorrhagic (severe) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Thrombocytopenia	grade 4, 66.7% DLT	18 g/m2 1 times / day multiple, intravenous (total) MTD Dose: 18 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 18 g/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090	unhealthy, 45 n = 6 Health Status: unhealthy Condition: Sarcoma Age Group: 45 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090
Neutropenia	grade 4, 83.3% DLT	18 g/m2 1 times / day multiple, intravenous (total) MTD Dose: 18 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 18 g/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090	unhealthy, 45 n = 6 Health Status: unhealthy Condition: Sarcoma Age Group: 45 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090
Infection	severe, 33.3% DLT	18 g/m2 1 times / day multiple, intravenous (total) MTD Dose: 18 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 18 g/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090	unhealthy, 45 n = 6 Health Status: unhealthy Condition: Sarcoma Age Group: 45 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10572607 Page: p.1090
Anemia	grade 4, 66.7% DLT	2.25 g/m2 1 times / day multiple, intravenous MTD Dose: 2.25 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 2.25 g/m2, 1 times / day Co-administed with:: doxorubicin, i.v(45 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	unhealthy, 45 n = 3 Health Status: unhealthy Condition: Breast cancer Age Group: 45 Sex: F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6
Neutropenia	grade 4, 66.7% DLT	2.25 g/m2 1 times / day multiple, intravenous MTD Dose: 2.25 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 2.25 g/m2, 1 times / day Co-administed with:: doxorubicin, i.v(45 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	unhealthy, 45 n = 3 Health Status: unhealthy Condition: Breast cancer Age Group: 45 Sex: F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6
Thrombocytopenia	grade 4, 66.7% DLT	2.25 g/m2 1 times / day multiple, intravenous MTD Dose: 2.25 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 2.25 g/m2, 1 times / day Co-administed with:: doxorubicin, i.v(45 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	unhealthy, 45 n = 3 Health Status: unhealthy Condition: Breast cancer Age Group: 45 Sex: F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6
Febrile neutropenia	grade 5, 33.3% DLT, Disc. AE	2.25 g/m2 1 times / day multiple, intravenous MTD Dose: 2.25 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 2.25 g/m2, 1 times / day Co-administed with:: doxorubicin, i.v(45 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6	unhealthy, 45 n = 3 Health Status: unhealthy Condition: Breast cancer Age Group: 45 Sex: F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11840607 Page: p.6
Cystitis hemorrhagic	severe Disc. AE	1.2 g/m2 1 times / day multiple, intravenous Recommended Dose: 1.2 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 1.2 g/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Testicular cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1
Nephrotoxicity	severe Disc. AE	1.2 g/m2 1 times / day multiple, intravenous Recommended Dose: 1.2 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 1.2 g/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Testicular cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1
Renal failure	severe Disc. AE	1.2 g/m2 1 times / day multiple, intravenous Recommended Dose: 1.2 g/m2, 1 times / day Route: intravenous Route: multiple Dose: 1.2 g/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Testicular cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf Page: p.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781	substrate 1037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2B6 664 CYP3A5 395 CYP2B1 12 CYP2C19 991 CYP2A6 543 CYP2C8 693 UGT 192 alcohol dehydrogenase 7 ALDH1 3 P-gp 1537 OCT2 355 OAT1 326 OAT3 339 MRP1 107

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1925	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/9157990/	yes
PXR 46	activator 214 Sources: https://pubmed.ncbi.nlm.nih.gov/24401834/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
OAT1 326	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21077648/	no
OAT3 339	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21077648/	no
P-gp 1537	substrate 3367 Sources: https://www.ingentaconnect.com/content/ben/cdth/2006/00000001/00000001/art00008	no
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25934575/	poor
ALDH1 3	substrate 3367 Sources: https://www.ingentaconnect.com/content/ben/cdth/2006/00000001/00000001/art00008	yes	Aldoifosfamide 3
CYP2A6 543	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.3109/03602539709037591?journalCode=idmr20	yes
CYP2B1 12	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10326030/	yes
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25934575/	yes
CYP2C8 693	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.3109/03602539709037591?journalCode=idmr20	yes
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15875221/	yes
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/26541366/	yes
OCT2 355	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21077648/	yes
UGT 192	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/20541539/	yes	4-HYDROXYIFOSFAMIDE 3
alcohol dehydrogenase 7	substrate 3367 Sources: https://www.ingentaconnect.com/content/ben/cdth/2006/00000001/00000001/art00008	yes	4-HYDROXYIFOSFAMIDE 3
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019763s020lbl.pdf#page=28 Page: 28.0	yes		no (co-administration study) Comment: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes inthe pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamidetherapy. (https://pubmed.ncbi.nlm.nih.gov/11503007/) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019763s020lbl.pdf#page=28 Page: 28.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019763s020lbl.pdf#page=28 Page: 28.0	yes		no (co-administration study) Comment: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes inthe pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamidetherapy. (https://pubmed.ncbi.nlm.nih.gov/11503007/) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019763s020lbl.pdf#page=28 Page: 28.0

PubMed

Title	Date	PubMed
Taurine attenuates fanconi syndrome induced by ifosfamide without compromising its antitumor activity.	1998	10063969
Anticancer drug sensitivity and expression of multidrug resistance markers in early passage human sarcomas.	1999 Aug	10473106
Deletions in the mitochondrial DNA and decrease in the oxidative phosphorylation activity of children with Fanconi syndrome secondary to antiblastic therapy.	1999 Jul	10401022
[Ifosfamide-related encephalopathy. Report of two cases].	1999 Mar	10216884
Primary desmoplastic small cell tumor of soft tissues and bone of the hand.	1999 Nov	10555010
A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer.	2001	11338879
Treatment of ruptured undifferentiated sarcoma of the liver in children: a report of two cases and review of the literature.	2001	11294295
Salvage chemotherapy in relapsed germ cell tumors.	2001 Apr	11374323
Treatment of patients with metastatic germ cell tumors relapsing after high-dose chemotherapy.	2001 Apr	11374314
[Post-operative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of German prospective randomised trial HIT'91].	2001 Apr	11355586
[Pigmented villonodular synovitis: apropos of 3 cases].	2001 Apr	11355581
Modified dorsalis pedis flap for coverage of a pretibial pressure sore after hip rotationplasty.	2001 Apr	11254426
Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma.	2001 Apr 1	11283932
A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.	2001 Feb 1	11157476
How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review.	2001 Feb 1	11157041
Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients.	2001 Feb 1	11157022
A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplantation.	2001 Feb 2	11161394
The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT).	2001 Feb-Mar	11165404
[Addisonian crisis as first manifestation of adrenal gland insufficiency in patient diagnosed with lung cancer].	2001 Jan	11387844
Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.	2001 Jan	11236809
Anticancer drug-induced kidney disorders.	2001 Jan	11219485
Recurrent germinoma in the optic nerve: report of two cases.	2001 Jan	11152350
Docetaxel and ifosfamide as second line treatment for patients with advanced or metastatic urothelial cancer after failure of platinum chemotherapy: a phase 2 study.	2001 Jan	11125366
Long-term stent implantation in a case of relapsing intrathoracic Ewing-sarcoma.	2001 Jan 15	11233473
A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma.	2001 Jun	11378339
Importance of surgery as salvage treatment after high dose chemotherapy failure in germ cell tumors.	2001 Jun	11371882
A preclinical model for experimental chemotherapy of human head and neck cancer.	2001 Jun	11351243
High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.	2001 Jun 1	11387352
Immunoglobulin D myeloma presenting as an extraosseous soft tissue tumor.	2001 Mar	11357456
Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.	2001 Mar 15	11251014
Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma.	2001 May 19	11377651
A novel alkylating agent, glufosfamide, enhances the activity of gemcitabine in vitro and in vivo.	2007 Aug	17786181

Patents

Sample Use Guides

In Vivo Use Guide

30-min infusion at a dose of 1.2 grams per m2 per day for 5 consecutive days

Route of Administration: Intravenous

In Vitro Use Guide

Human testicular germ cell tumour lines H 12.1 and 2102 EP were treated with ifosfamide at 50 mg kg-1 day-1.

Name

Type

Language

IFOSFAMIDE

Official Name

English

Z4942

Code

English

2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE, N,3-BIS(2-CHLOROETHYL)TETRAHYDRO-, 2-OXIDE

Systematic Name

English

NSC-109724

Code

English

ISOCYCLOPHOSPHAMIDE

Common Name

English

3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide

Systematic Name

English

IFOSFAMIDE [USP-RS]

Common Name

English

ifosfamide [INN]

Common Name

English

IFOSFAMIDE [USAN]

Common Name

English

IFOSFAMIDE [USP MONOGRAPH]

Common Name

English

IFOSFAMIDE [EP IMPURITY]

Common Name

English

MJF 9325

Code

English

IFOSFAMIDE [MART.]

Common Name

English

MJF-9325

Code

English

IFOSFAMIDE [JAN]

Common Name

English

Ifosfamide [WHO-DD]

Common Name

English

Z-4942

Code

English

IFOSFAMIDE [MI]

Common Name

English

N,3-BIS(2-CHLOROETHYL)TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE 2-OXIDE

Systematic Name

English

IFOSFAMIDE [EP MONOGRAPH]

Common Name

English

IFOSFAMIDE [HSDB]

Common Name

English

ISOPHOSPHAMIDE [IARC]

Common Name

English

IFOSFAMIDE [ORANGE BOOK]

Common Name

English

IFOSFAMIDE [VANDF]

Common Name

English

IFEX

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C697