Ifosfamide

Toxicity

LD50 (mouse) = 390-1005 mg/kg, LD50 (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

Chemical properties

Crystalline Solid

Originator

Holoxan,Lucien,France,1976

The Uses of Ifosfamide

A cytostatic agent, related structurally to cyclophosphamide

The Uses of Ifosfamide

antibacterial

The Uses of Ifosfamide

Ifosphamide USP (Ifex)is used to treat germ cell testicular cancer; used in combination with mesna.

Background

Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. It is active as an alkylating agent and an immunosuppressive agent.

Indications

Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma.

What are the applications of Application

Ifosfamide is a cytostatic agent structurally related to cyclophosphamide

Definition

ChEBI: The simplest member of the class of ifosfamides that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by 2-chloroethyl groups on both the nitrogen atoms respectively. It is a nitrogen mustard alkylating agent used in the treatment of advanced breast c ncer.

Indications

Ifosfamide (Ifex) is an analogue of cyclophosphamide that requires metabolic activation to form 4-hydroxyifosfamide. In general, the metabolism, serum half-life, and excretion of ifosfamide are similar to those of cyclophosphamide.
Ifosfamide is active against a broad spectrum of tumors, including germ cell cancers of the testis, lymphomas, sarcomas, and carcinomas of the lung, breast, and ovary. It is thought to be more active than cyclophosphamide in germ cell cancers and sarcomas.
Ifosfamide is less myelosuppressive than cyclophosphamide but is more toxic to the bladder. It also may produce alopecia, nausea, vomiting, infertility, and second tumors, particularly acute leukemias. Neurological symptoms including confusion, somnolence, and hallucinations have also been reported. It is recommended that ifosfamide be coadministered with the thiol compound mesna (Mesnex) to avoid hemorrhagic cystitis.

Manufacturing Process

127.6 g (1.1 mols) of N-(2-chloroethyl)-amine hydrochloride are suspended in a solution of 218 g (1 mol) of N-(2-chloroethyl)-N,O-propylene phosphoric acid ester amide monochloride in 600 cc of methylene dichloride, and 212 g of triethylamine are added thereto dropwise with stirring. The reaction mixture is heated to boiling by the reaction heat. After termination of the addition, the reaction mixture is heated to boiling for another 2 hours. Thereafter, it is cooled to room temperature and the precipitated triethylamine hydrochloride is separated by filtration with suction. The filtrate is extracted with about 60cc of dilute hydrochloric acid (pH 3), then twice with about 60 cc of water, thereafter with about 60 cc of dilute soda lye and finally twice with about 60 cc of water. After drying over anhydrous sodium sulfate, methylene dichloride is distilled off under normal pressure. The oily residue is dried in a vacuum and thereafter extracted in a perforator with 500 cc of anhydrous ether. The oily extract crystallizes upon inoculation and standing in an ice box. After standing for several hours, the precipitate is filtered off, washed with a small amount of cold ether and dried in a vacuum at room temperature. Yield: 185 g (71% of the theoretical). This material is also identified as 3-(2- chloroethyl)-2-(2-chloroethylamino)-tetrahydro-2H-1,3,2-oxazaphosphorin-2- oxide; generic name: ifosfamide. F.P.: 39°C to 41°C.

brand name

Ifex (Bristol-Myers Squibb).

Therapeutic Function

Antineoplastic

General Description

Ifosfamide is available in 1- and 3-g vials for IV administrationas Food and Drug Administration (FDA)-approvedthird-line therapy in the treatment of testicular cancer. It has also been utilized (although not FDA approved) in the treatmentof a wide variety of cancers including Hodgkin’s andnon-Hodgkin’s lymphoma, soft tissue sarcoma, germ celltumors, small cell lung cancer, non–small cell lung cancer(NSCLC), cancers of the head and neck, bladder cancer, cervicalcancer, and Ewing sarcoma. Coadministration ofmesna is recommended. The mechanisms of resistance areidentical to those seen with cyclophosphamide. The drug iswidely distributed with a low extent of protein binding(20%). Metabolism primarily by CYP3A4/5 and CYP2B6 isrequired for activation of the compound. Theagent is administered as the racemic mixture as a result ofthe presence of the chiral phosphorus atom, and differentialmetabolism of the R- and S-isomers has been observed. Incontrast to cyclophosphamide, there is a greater amount ofdeactivation of the agent by N-dechloroethylation and subsequentlymore chloroacetaldehyde is produced, which mayresult in a greater amount of neurotoxicity and nephrotoxicitythan seen with cyclophosphamide. The N-dechloroethylatedmetabolites are the predominate species seen in theplasma. The parent and metabolites are eliminated inthe urine with an elimination half-life of 3 to 10 hours. Themajor components found in the urine are the dechlorethylatedmetabolites. Dose-limiting toxicities include myelosuppressionand bladder toxicity. Other adverse effectsinclude nausea, alopecia, amenorrhea, inappropriate secretionof antidiuretic hormone, as well as the production ofsecondary cancers. Neurotoxicity, which is associated withthe production of chloroacetaldehyde presents as confusion,seizure, weakness, and hallucination, and coma may occur.

Pharmacokinetics

Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific.

Clinical Use

Ifosamide currently is used as “third-line” therapy against testicular cancer, although it also has shown activity in a number of solid tumors and hematologic cancers.

Side Effects

Patients on ifosfamide (but not cyclophosphamide) commonly exhibit central nervous system (CNS) toxicity. In severe forms, CNS depression can progress to coma and death.

Synthesis

Ifosfamide, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2- oxazaphosphorin-2-oxide (30.2.1.17), which is viewed as an isomeric compound of cyclophosphamide (30.2.1.15) and which is analogous in terms of action, is made by reacting N-(2-chloroethyl)-N-(3-hydroxypropyl)amine with phosphorous oxychloride, giving 3-(2-chloroethyl)-2-chlorotetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide (30.2.1.16), which is reacted with N-(2-chloroethyl)amine, forming the desired ifosfamide (30.2.1.17).

Veterinary Drugs and Treatments

In small animals, ifosfamide may be of benefit as part of treatment protocols for a variety of neoplasms. Treatment of lymphomas and soft tissue sarcomas with ifosfamide in dogs and cats has been investigated to some extent; some efficacy has been demonstrated.
In humans, ifosfamide is used in various treatment protocols for testicular neoplasms, bone and soft tissue sarcomas, bladder cancer, lung cancer, cervical cancer, ovarian cancer, and some types of lymphomas.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced effect of coumarins.
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).

Metabolism

Primarily hepatic. Ifosfamide is metabolized through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.

Metabolism

The pharmacokinetics of ifosfamide are reported to exhibit considerable inter-individual variation. It is a prodrug that is extensively metabolised, chiefly by cytochrome P450 isoenzymes CYP3A4 and CYP2B6 in the liver, to both active and inactive alkylating metabolites; there is some evidence that metabolism is saturated at very high doses. After repeated doses (fractionated therapy) there is a decrease in the elimination half-life, apparently due to auto-induction of metabolism. It is excreted largely in urine, as unchanged drug (80%) and metabolites.