Ifosfamide

261.09

261.09

223-237-3

759154|109724

DTXSID7020760

Crystals from anhyd ether|White crystalline powder

L01AA06|L - Antineoplastic and immunomodulating agents

2934999090

41.6

0.9

Solid

1.3±0.1 g/cm3

39-41 °C

336.1°C at 760 mmHg

157.1±30.7 °C

1.506

1.50e+01 g/L

2-8°C

LD50 in rats (mg/kg): 160 i.p. (Arnold, 1973); also reported as 150 i.p. (Brock)

147 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Ⅲ

6.1(b)

3249

3

25-36

26-45

RP6050000

T

/It was/ reported that ifosfamide 80 mg/ml in sodium chloride 0.9% is chemically stable, exhibiting about a 7% loss in none days at 37 deg C in the dark. Ifosfamide 0.6 & 20 mg/ml in dextrose 5% in water, Ringer's injection. lactated, sodium chloride 0.9%, or sterile water for injection, polypropylene syringes, is physically & chemically stable for at least 24 hr at 30 deg C. Constitution to an ifosfamide concn of 100 mg/ml with benzyl alcohol-preserved bacteriostatic water for injection resulte

Missing Phrase - N15.00950417-P305 + P351 + P338

H301-H319

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

|Danger|H301 (98.91%): Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P280, P301+P310, P305+P351+P338, P321, P330, P337+P313, P405, and P501|Aggregated GHS information provided by 92 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Ifosfamide was detected at a concentration of 24 ng/l in treated hospital effluent from a sewage treatment plant(1). Concentrations of ifosfamide in effluent from a tumor biology hospital in Germany ranged from not detected to 1,914 ng/l during 7 days of sampling in January through April, 1995(2).

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).

The toxicity of ifosfamide seems to be similar to that of cyclophosphamide. Mild and transient elevations in serum aminotransferase levels are found in a high proportion of patients receiving ifosfamide. Because ifosfamide is typically given in combination with other antineoplastic agents, its role in causing the serum enzyme elevations is often not clear. The abnormalities are generally transient, do not cause symptoms and do not require dose modification. Clinically apparent liver injury from ifosfamide has been limited to a small number of cases of cholestatic hepatitis arising within a few weeks of receiving ifosfamide (with other antineoplastic agents). In addition, sinusoidal obstruction syndrome has been reported after conditioning regimens that have included ifosfamide in preparation for hematopoietic cell transplantation. The onset of injury is usually within one to three weeks of the myeloablation and is characterized by a sudden onset of abdominal pain, weight gain, ascites, marked increase in serum aminotransferase levels (and lactic dehydrogenase), and subsequent jaundice and hepatic dysfunction. The severity of sinusoidal obstruction syndrome varies from a transient, self limited injury to acute liver failure. The diagnosis is usually based on clinical features of tenderness and enlargement of the liver, weight gain, ascites and jaundice. Liver biopsy is diagnostic but often contraindicated, because of severe thrombocytopenia after bone marrow transplantation.

The more urotoxic agent ifosfamide was introduced to the market with the uroprotective agent, Mesna. Mesna liberated free thiol groups in the bladder which then can react with & neutralize the oxazaphosphorine metabolite. When administered in an appropriate dosing schedule, Mesna can prevent the bladder toxicity completely.|BACKGROUND: The autoinducible metabolic transformation of the anticancer agent ifosfamide involves activation through 4-hydroxyifosfamide to the ultimate cytotoxic ifosforamide mustard and deactivation to 2- and 3-dechloroethylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde. Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by CYP3A4 and CYP2B6. The aim of this study was to investigate modulation of the CYP-mediated metabolism of ifosfamide with ketoconazole, a potent inhibitor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. METHODS: In a double-randomized, 2-way crossover study a total of 16 patients received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatment and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethylifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data analysis was performed with a population pharmacokinetic model with a description of autoinduction of ifosfamide. RESULTS: Rifampin increased the clearance of ifosfamide at the start of therapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, whereas exposure to the metabolites was decreased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketoconazole did not affect the fraction metabolized or the exposure to the dechloroethylated metabolites, whereas both parameters were reduced with 4-hydroxyifosfamide. CONCLUSIONS: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.|Leukopenic and/or thrombocytopenic effects of ifosfamide may be increased with concurrent or recent therapy if these medications /blood dyscarasia-causing medications/ cause the same effects; dosage adjustments of ifosfamide, if necessary, should be based on blood counts.|Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with ifosfamide/.|For more Interactions (Complete) data for IFOSFAMIDE (7 total), please visit the HSDB record page.

LD50 Rat oral 143 mg/kg|LD50 Rat ip 140 mg/kg|LD50 Rat sc 160 mg/kg|LD50 Rat iv 190 mg/kg|For more Non-Human Toxicity Values (Complete) data for IFOSFAMIDE (8 total), please visit the HSDB record page.

Ifosfamide shows little plasma protein binding.

Ifosfamide's production and use as an antineoplastic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a log Kow of 0.86(2) and a regression-derived equation(3), indicates that ifosfamide is expected to have high mobility in soil(SRC). Volatilization of ifosfamide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Ifosfamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-5 mm Hg(SRC), determined from a fragment constant method(5). Ifosfamide has been shown to be non-biodegradable in laboratory-scale sewage treatment studies(6), therefore biodegration in soil may not be an important environmental fate process(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a log Kow of 0.86(2) and a regression-derived equation(3), indicates that ifosfamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Ifosfamide may hydrolyze as indicated by a neutral hydrolysis calculated half-life for analogous cyclophosphamide at 25 °C of 41 days(8). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Ifosfamide has been shown to be non-biodegradable in laboratory-scale sewage treatment studies(7), therefore biodegration in water may not be an important environmental fate process(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ifosfamide, which has an estimated vapor pressure of 3.0X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase ifosfamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 9 hrs(SRC), calculated from its rate constant of 4.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase ifosfamide may be removed from the air by wet and dry deposition(SRC).

The rate constant for the vapor-phase reaction of ifosfamide with photochemically-produced hydroxyl radicals has been estimated as 4.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 9 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ifosfamide may hydrolyze as indicated by a neutral hydrolysis calculated half-life for analogous cyclophosphamide at 25 °C of 41 days(2). Direct photolysis is not expected due to the lack of absorption in the environmental UV spectrum (>290 nm).

An estimated BCF of 3 was calculated for ifosfamide(SRC), using a log Kow of 0.86(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of ifosfamide is estimated as 70(SRC), using a log Kow of 0.86(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that ifosfamide is expected to have high mobility in soil.

The Henry's Law constant for ifosfamide is estimated as 1.4X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that ifosfamide is expected to be essentially nonvolatile from water surfaces(2). Ifosfamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-5 mm Hg(SRC), determined from a fragment constant method(3).

DRINKING WATER: Ifosfamide was not detected in twelve drinking water samples from facilities in Germany, detection limit of 0.010 ug/l(1).|SURFACE WATER: Ifosfamide was not detected in water samples from the Weschnitz River in the Hessian Ried, Germany(1).

Occupational exposure to ifosfamide may occur through inhalation and dermal contact with this compound at workplaces where ifosfamide is produced or used. (SRC)

Ifosfamide (along with cyclophosphamide) was detected in the urine of 8 pharmacy technicians and nurses at amounts ranging from <0.001-0.5 ug(1). 21 nurses and pharmacy personnel in a Munich, Germany hospital were monitored for compound exposure; on days when 5,900 mg/l ifosfamide was mixed, 4 of 21 urine samples tested positive with concentrations ranging from 5 to 12.7 ug/24 hr urine(2).

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.|Drug: Ice|Drug: Ifosfamide|Drug: R-ice|Drug: Veip|Drug: Vip

Ifosfamide is a parenterally administered alkylating agent similar to cyclophosphamide that is used in the treatment of several forms of cancer including lymphomas, sarcoma and advanced forms of solid organ cancer such as breast, testicular, ovarian, gastric and lung cancer. Ifosfamide therapy is associated with minor transient serum enzyme elevations and has been linked to cases of acute liver injury, including acute cholestatic hepatitis and veno-occlusive disease.

Antineoplastic Agents, Alkylating Agents

Ifosfamide currently is approved for use in combination with other drugs for germ cell testicular cancer & is widely used to treat pediatric & adult sarcomas. Clinical trials also have shown ifosfamide to be active against carcinomas of the cervix & lung & against lymphomas. It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result form a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).|Ifosfamide is indicated, in combination with other antineoplastic agents and a prophylactic agent against hemorrhagic cystitis (such as mesna), for treatment of germ cell testicular tumors. /Included in US product labeling/|Ifosfamide is indicated as reasonable medical therapy for treatment of head and neck carcinoma. (Evidence rating: IIID) /NOT included in US product labeling/|Ifosfamide is used for treatment of soft-tissue sarcomas, Ewing's sarcoma, and Hodgkin's and non-Hodgkin's lymphomas. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for IFOSFAMIDE (9 total), please visit the HSDB record page.

It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result form a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).|Ifosfamide is distributed into breast milk. Breast feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).|The bone marrow depressant effects of ifosfamide may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.|Many side effects of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.|For more Drug Warnings (Complete) data for IFOSFAMIDE (20 total), please visit the HSDB record page.

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.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)

Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.|Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2.|2.4±0.33 L/h/m^2 [pediatric patients]|Renal excretion & t1/2 are dose & schedule dependent. 60-80% recovered as unchanged drug or metabolite in urine within 72 hr after admin.|The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m(2)/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (+/-sem) in vitro and in vivo erythrocyte (e)-plasma (p) partition coefficients (P(e/p)) were 0.75+/-0.01 and 0.81+/-0.03, 0.62+/-0.09 and 0.73+/-0.05, 0.76+/-0.10 and 0.93+/-0.05 and 1.38+/-0.04 and 0.98+/-0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUC(e/p)) were 0.96+/-0.03, 0.87+/-0.07, 0.98+/-0.06 and 1.34+/-0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies.|... To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. ... Pharmacokinetic assessment followed by model fitting. Patients: The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. ... A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. ... Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. ... We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.|... The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. ... Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. ... The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.|For more Absorption, Distribution and Excretion (Complete) data for IFOSFAMIDE (6 total), please visit the HSDB record page.

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.|Like cyclophosphamide, ifosfamide is activated in the liver by hydroxylation. However, the activation of ifosfamide proceeds more slowly, with greater production of dechlorinated metabolites & chloroacetaldehyde. These differences in metabolism likely account for the higher doses of ifosfamide required for equitoxic effects & the possible difference in antitumor spectrum of the two agents.|Like cyclophosphamide, isophosphamide requires metabolism by microsomal enzymes to act as a cytotoxic agent. It is rapidly metabolized in many species, including rodents and dogs; the urinary metabolites indicate that a series of reactions take place analogous to those in the metabolism of cyclophosphamide. Acrolein is produced during its oxidative degradation, and one product of the reaction is the ring-opened carboxy derivative. Dogs also rapidly metabolize isophosphamide, and the carboxy derivative and 4-keto isophosphamide have been identified in the urine.|The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.|The anticancer drug ifosfamide is a prodrug requiring activation through 4-hydroxyifosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of ifosfamide leads to 2- and 3-dechloroethylifosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for ifosfamide and increased for 3-dechloroethylifosfamide compared with short infusion durations. No differences in dose-normalized exposure to ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylifosfamide. The observed dose and infusion duration dependence should be taken into account when modeling ifosfamide metabolism.|Ifosfamide is a known human metabolite of L-trofosfamide.

7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.|The elimination half-life associated with doses of 2.5 g/sq m is 6-8 hr, whereas the elimination half-life associated with doses of 3.5-5 g/sq m is 14-16 hr.

The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death.|Mechanism of action: metabolites cause alkylation of DNA. /from table/|Ifosfamide, a structural analog of cyclophosphamide, belongs to the oxazaphosphorine class of antitumor alkylating agents which must be activated by the mixed function oxidase system of the liver. The 4-hydroxy oxazaphosphorines are a reactive species capable of interacting with nucleic acids & cellular materials to cause cell damage & death. The 4-hydroxy metabolite spontaneously liberates acrolein in many sites throughout the body & it is this substance that is responsible for oxazaphosphorine urotoxicity. Both ifosfamide & cyclophosphamide produce cystitis characterized by tissue edema & ulceration followed by sloughing of mucosal epithelial cells, necrosis of smooth muscle fibers & arteries, & culminating in focal hemorrhage. The selective urotoxicity of oxazaphosphorine occurs because the bladder contains a very low concn of thiol cmpds (glutathione, cysteine) which, by virtue of their nucleophilic sulfhydryl groups, are able to react & neutralize many reactive chemicals. Because the metabolic activation of ifosfamide proceeds more slowly than that of cyclophosphamide, doses of ifosfamide are 3-4 times higher than those of cyclophosphamide. This explains the higher incidence of urotoxicity associated with ifosfamide.

There are no antidotes for ifosfamide of its metabolites. Dialysis may be considered in view of the favorable toxicokinetics (low apparent volume of distribution),but no studies are yet available to confirm this.|/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A serious undesired effect of certain cytostatics is their nephrotoxicity. In this study, we investigated the toxic effects of ifosfamide and cisplatin by clinical and biochemical parameters in relation to (99m)Tc-dimercaptosuccinic acid ((99m)Tc-DMSA) and Tc(99m)N, N-ethylenedicysteine (EC) renal scintigraphy. The indicators were urinary beta2-microglobulin levels, tubular resorption of phosphate, urinary protein and glucose excretion, glomerular filtration rate, urinary pH and osmolarity. Thirteen paediatric patients (seven boys and six girls), aged 2-16 years, were investigated. Five patients received only cisplatin, six patients were treated with ifosfamide and cisplatin and two with ifosfamide and carboplatin for various malignancies. All except three patients had normal DMSA uptake (median, 19; range, 16-29%) prior to chemotherapy. The reduction in DMSA uptake was unilateral due to tumour invasion in those three patients. Following chemotherapy, DMSA uptake showed reduction in five patients with or without clinical nephrotoxicity. The observed pattern was decreased renal uptake and elevated bladder activity. Three patients with decreased DMSA uptake had normal tubular maximum phosphate reabsorption, which suggested subclinical injury. Decrease in DMSA uptake and tubular phosphate reabsorption (TPR) was detected simultaneously in two patients. No abnormalities were seen on Tc(99m)-EC scintigraphy to suggest nephrotoxicity in our investigation. However, Tc(99m)-EC clearly demonstrated a reduction in split renal function in children with tumour invasion. In summary, we found that ifosfamide induced tubular injury can be detected with (99m)Tc-DMSA scintigraphy before chemotherapy associated nephrotoxicity is observed by laboratory measurements. Our results also imply that, although a tubular agent, renal scintigraphy performed with Tc(99m)-EC is not able to detect subclinical injury or predict the outcome during treatment.|BACKGROUND: Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children and young adults. Used at high doses (HDI) the drug may cause severe multiorgan toxicity. Peripheral neuropathy is a less well-known side effect that may limit its use. We describe a 16-year-old girl with a Ewing sarcoma who was given post-operative treatment with HDI (15 mg/m(2) infused over 5 days). After the second course she experienced paresthesias in both feet. After the third course she developed signs of severe toxicity in the CNS, kidneys, heart, and severe pain in her feet. PROCEDURE: Neurologic and neurophysiologic investigations, including neurographic studies of motor and sensory nerves, EMG, and thermotest, were performed in the acute phase and after 6 and 21 months, respectively. Renal and cardiac function was also assessed. RESULTS: She developed generalized weakness of the arms and legs and an extremely painful hyperesthesia of the soles. The symptoms improved gradually during follow-up but remained to some extent even after more than 2 years. Serial neurophysiologic investigations indicated classical signs of axonal neuropathy, which tended to improve during follow-up. After 18 months the glomerular filtration rate and the effective renal plasma flow were 30 and 12% of normal, respectively, while other organ functions had returned to baseline. CONCLUSIONS: Symptoms of peripheral neuropathy after HDI may herald severe multiorgan toxicity, if continued. Early administration of anesthetics through the intrathecal route should be considered in case of ifosfamide-induced painful peripheral neuropathy.|The renal functions in pediatric cancer patients who received ifosfamide (IFO) treatment were evaluated and the risk factors related to IFO nephrotoxicity were determined. The medical records of all children treated with IFO were reviewed, and 62 with normal renal function before IFO treatment were selected. Nephrotoxicity was diagnosed by measuring urine beta2-microglobulin and glucose, and serum phosphate, bicarbonate, and creatinine. Forty-eight (77.4%) had a history of previous cisplatin treatment. Nephrotoxicity was detected in 20 patients (32.3%). beta2-Microglobulinuria was observed in all 20, hypophosphatemia in 10 (16.1%), hypocarbia in 2 (3.2%), glucosuria in 5 (8.1%), and decreased creatinine clearance in 7 (11.3%). The cumulative dose of IFO and a history of previous cisplatin therapy were related to nephrotoxicity. Among the 20 patients with nephrotoxicity, the median cumulative dose of IFO in patients with a low (<500 mg/m2) and high (>500 mg/m2) cumulative dose of previous cisplatin was 80 g/m2 (73-102 g/m2) and 45 g/m2 (11-76 g/m2), respectively. Most of the nephrotoxicity persisted after cessation of IFO treatment. In conclusion, close monitoring of IFO nephrotoxicity should be started earlier in patients with high-dose cisplatin pretreatment. Tubular proteinuria, as indicated by beta2-microglobulinuria, was the most-sensitive marker for IFO nephrotoxicity. Long-term follow-up study for reversibility of IFO nephrotoxicity is in progress.|A case of a child with growth retardation and prolonged osteomalacia, as a result of chronic renal tubulopathy, following successful therapy for a sacral-coccygeal germinal tumour, is described. The male patient was enrolled into the research programme for the evaluation of the association between deletion of the genes encoding a number of classes of glutathione S-transferases (GST) and adverse reactions to alkylating agents. His genotype revealed the genes encoding glutathione transferase classes GSTM1 and GSTT1, but these enzymes did not provide adequate protection for the tubular cells, from the toxic effects of ifosfamide metabolites. Intense chemotherapy resulted in an increased risk of chronic side effects. Further studies are necessary for increased understanding of the inter-individual variability in the extent and nature of ifosfamide nephrotoxicity.

Asta Z 4942

An amount consumed of 290 kg/yr was calculated for Germany.

Has approx one-third the alkylating activity of cyclophosphamide and requires hepatic microsomal conversion to its active form.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients