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PubMed2003

Ifosfamide pharmacokinetics and hepatobiliary uptake in vivo investigated using single- and double-resonance 31P MRS.

MRS has considerable potential for the measurement of drug pharmacokinetics in vivo. In this study single- and double-resonance (31)P MRS was used to investigate the biodistribution, pharmacokinetics, and metabolism of ifosfamide following administration of 500 mg/kg ifosfamide in guinea pigs. (1)H-decoupling was found to nearly double the signal of detected peaks. However, in contrast to studies of ifosfamide in solution, the polarization transfer sequence gave no further signal enhancements. This was attributed to significantly reduced relaxation times in vivo. Chemical shift imaging (CSI) measurements showed that significant proportions of ifosfamide-related (31)P MRS signals arose from the liver, as expected, but also from the gall bladder, which was not predicted from the current literature. Signals were observed within 5 min of the end of administration. The halflife in liver was approximately 74 min, whereas in gall bladder there was no measurable signal decay during the 2.5-hr studies. High-resolution (31)P MRS of bile showed that the "ifosfamide" peak in vivo consists of at least two compounds. The lower-concentration peak is ifosfamide, and an investigation is under way to identify the higher-concentration peak. Other peaks observed in bile are tentatively assigned to carboxy-ifosfamide and dechloroethyl-ifosfamide. Overall, (1)H-decoupled (31)P MRS has proved to be a useful tool for investigating the metabolism of ifosfamide in vivo.

Animals↗
PubMed2004

Influence of age upon Ifosfamide-induced nephrotoxicity.

BACKGROUND: Ifosfamide-induced nephrotoxicity is well recognized in children, although it has also been reported in adults. Whether ifosfamide nephrotoxicity is more common in children than in adults is not known. PROCEDURE: Medical records of adults and children diagnosed with sarcoma whom received ifosfamide with a cumulative dose >20 g/m(2) were evaluated. Twenty-five children (</=18-years of age) and 28 adults were identified. RESULTS: National Cancer Institute Common Toxicity Criteria grade 3-4 ifosfamide-induced nephrotoxicity was present in 24 and 17% of children and adults, respectively (P = 0.58). Cumulative ifosfamide doses were similar between the two populations, with the median (range) of 70.2 g/m(2) (22.4-72) for children and 59 g/m(2) (20.8-146) for adults (P = 0.25). Logistic regression analysis indicated that neither age or cumulative ifosfamide dose were associated with grade 3-4 ifosfamide-induced nephrotoxicity (P = 0.36). CONCLUSIONS: Children and adults receiving >20 g/m(2) of ifosfamide have similar susceptibility to ifosfamide-induced nephrotoxicity. Factors other than age and cumulative dose should be considered for understanding the inter-individual variation in nephrotoxicity.

Adolescent↗
PubMed1991

Ifosfamide pharmacokinetics.

This review examines and details the pharmacokinetics of ifosfamide (a congener of cyclophosphamide) when administered by a number of commonly used chemotherapeutic regimes. The influence of route of administration, schedule of administration and dose on the pharmacokinetics of ifosfamide and its metabolites are discussed. Oral fractionated ifosfamide therapy, which causes an excessively high incidence of neurotoxicity, is similar to intravenous fractionated therapy in that it exhibits a time dependent increase in ifosfamide metabolic clearance. Five g/m2 ifosfamide given intravenously as a short (half hour) or long (24 hr) infusion does not exhibit dose dependent (zero-order) pharmacokinetics. In patients who develop ifosfamide/mesna associated CNS toxicity the pharmacokinetics of parent ifosfamide are not aberrant. This implies that ifosfamide metabolites are more likely to be responsible for the neurotoxicity rather than the parent drug. The development of simple and more specific analytical methodology, will allow further studies of the pharmacokinetics of the active ifosfamide metabolite(s). This may lead to further optimisation of the therapeutic index of ifosfamide treatment.

Administration, Oral↗
PubMed1991

Metabolism and pharmacokinetics of oral and intravenous ifosfamide.

The initial metabolism of ifosfamide (IF) consists of two different pathways: enzymatic hydroxylation at carbon-4 forms the cytostatically active metabolite 4-OH-IF ("activated ifosfamide") whereas side-chain oxidation results in the liberation of chloroacetaldehyde, a compound with possible neurotoxic properties. The pharmacokinetics of ifosfamide and its activated form were investigated in 12 cancer patients, who received both oral and i.v. treatment in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n = 7) or 1.5 g/m2 (n = 5). In 3 patients the pharmacokinetics of chloroacetaldehyde were also investigated. After oral application, ifosfamide absorption proceeded rapidly, the oral bioavailability was 0.92. Independent of the route of ifosfamide application on day 1, the terminal half-life on day 3 (when the drug was given by the alternative route) was decreased in 6 out of the 12 patients, thus indicating self-induction of hepatic metabolism. 4-OH-IF was already present 20 min after ifosfamide administration. In the individual patient the concentrations of 4-OH-IF were always higher after oral than after i.v. IF application: the mean p.o.:i.v. ratios for cmax and the area under the concentration/time curve were 2.3 and 1.7 respectively (P less than 0.05). In a first series of 3 patients the chloroacetaldehyde concentrations measured after oral ifosfamide application were about twice as high as those when the drug was given intravenously. These results indicate that (in comparison to the i.v. route) orally administered ifosfamide may be more cancerotoxic but also leads to higher levels of chloroacetaldehyde. This would explain the neurotoxic side-effects previously seen after oral administration of comparatively low ifosfamide doses.

Acetaldehyde↗
PubMed1999

Effects of 4-hydroperoxy ifosfamide in combination with other anticancer agents on human cancer cell lines.

Ifosfamide is one of the currently available anticancer agents with a broad spectrum of clinical activity against a variety of tumors. To investigate its optimal combinations, we studied the effect of 4-hydroperoxy ifosfamide (the active form of ifosfamide) in combination with other anticancer agents against two human cancer cell lines, MG-63 (an osteosarcoma cell line) and MOLT-3 cells (a T-cell leukemia cell line). The cells were incubated for 4 days and 3 days, respectively, in the presence of 4-hydroperoxy ifosfamide and the other agent. Cell growth inhibition was determined by MTT assay. The effects of these drug combinations at the concentration producing 50% inhibition (IC50) were analyzed by the isobologram method. 4-Hydroperoxy ifosfamide showed additive effects with bleomycin, cisplatin, cytarabine, doxorubicin, etoposide, 5-fluorouracil, and mitomycin C, while it showed a protective effect with methotrexate in both cell lines. 4-Hydroperoxy ifosfamide showed an additive effect with vincristine in the MG-63 cell line, while it showed a sub-additive effect in the MOLT-3 cell line. No anticancer agents tested showed a supra-additive effect with 4-hydroperoxy ifosfamide. These data suggest that ifosfamide is advantageous for simultaneous administration with a majority of the anticancer agents we studied. Methotrexate is an inappropriate drug for simultaneous administration with ifosfamide.

Antineoplastic Agents, Alkylating↗
PubMed1989

Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study).

A phase II trial of ifosfamide (isophosphamide, NSC 109724) and mesna (2-mercaptoethane sodium sulfonate, NSC 113891) in women with advanced or recurrent mixed mullerian tumors of the uterus was conducted by the Gynecologic Oncology Group. The starting dose of ifosfamide was 1.5 gm/m2 daily, intravenously, for 5 days. The starting dose of ifosfamide was reduced 1.2 gm/m2 daily in patients who had received prior radiotherapy. Mesna was given intravenously immediately and at 4 and 8 hours after the administration of ifosfamide. Each mesna dose was 20% of the total daily dose of ifosfamide. Twenty-nine patients are evaluable for toxicity, and 28 patients are evaluable for response. Twenty-one patients had received prior abdominal hysterectomy, and eight patients had prior radiotherapy. Thirteen tumors were homologous and 15 heterologous. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in seven (25%) patients and two (7.1%) had grade 3 or 4 thrombocytopenia. Two patients (7.1%) had grade 3 or 4 neurotoxicity. One patient experienced lethargy and confusion that responded to discontinuation of the ifosfamide. A second patient developed progressive cerebellar dysfunction, left hemiparesis, and coma. This patient died after 3 days of therapy. Complete responses were seen in five (17.9%) patients and partial responses occurred in four (14.3%) patients for a total response rate of 32.2%. These results indicate that ifosfamide is an unusually active drug in patients with advanced or recurrent mixed mullerian tumors of the uterus. Studies with combination regimens incorporating ifosfamide are warranted. The toxicity of ifosfamide in Gynecologic Oncology Group studies is being evaluated retrospectively.

Adult↗
PubMed2001

Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin.

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.

Adult↗
PubMedDate not supplied

Efficacy and tolerability of the ifosfamide-epirubicin combination in relapsed ovarian cancer.

A retrospective study evaluating the efficacy and tolerability of epirubicin-ifosfamide (EI) in patients with relapsed advanced ovarian cancer (ROC) after prior chemotherapy was conducted. A total of 93 patients received epirubicin (50 mg/m(2), day 1), ifosfamide (1500 or 2500 mg/m(2), days 1-3), and mesna monthly. Thirty-five percent had received one line of chemotherapy (platinum 100%, taxanes 8%); 38%, two lines; and 27%, more than two lines. Fifty-three percent received 2500 mg/m(2)/day ifosfamide and 47% received 1500 mg/m(2)/day ifosfamide. Ifosfamide was administered by continuous infusion in 12 patients. Mean number of courses was 4 (1-12). Grade 4 toxicity was 69% neutropenia and 12% thrombocytopenia. Three patients on high-dose ifosfamide as a short infusion had central nervous system dysfunction resulting in death. There were 84 assessable patients: 7 (8%), complete responses; 13 (15%), partial responses; and 20 (24%), stable disease. Median time to progression was 5 months (3 days to 36 months). The EI combination appears to be effective in ROC. However, toxicity with high-dose ifosfamide administered by short infusion is not acceptable. Tolerability can be improved using ifosfamide at 1500 mg/m(2) by continuous infusion. The combination of ifosfamide with newer anthracycline agents such as liposomal doxorubicin may be an alternative and needs further evaluation for use after first-line taxane-based chemotherapy.

Adolescent↗
PubMed2005

Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation.

Ifosfamide nephrotoxicity is attributed to the formation of a toxic metabolite, chloroacetaldehyde, via N-dechloroethylation, a reaction that is purportedly catalyzed by CYP3A and CYP2B6. Because allelic variants of CYP3A5 are associated with polymorphic expression of microsomal CYP3A5 in human liver and kidneys, we hypothesized that ifosfamide N-dechloroethylation depends on CYP3A5 genotype. We compared ifosfamide N-dechloroethylation activity in cDNA-expressed CYP3A4 and CYP3A5. Ifosfamide N-dechloroethylation was also assessed in liver (N = 20) and kidney (N = 21) microsomes from human donors with different CYP3A5 genotypes. Ifosfamide N-dechloroethylation was catalyzed by recombinant CYP3A5 at a rate comparable with recombinant CYP3A4. In human liver microsomes matched for CYP3A4 protein content, N-dechloroethylation was more than 2-fold higher in that from donors carrying CYP3A5*1 allele that express CYP3A5 relative to that from donors homozygous for the mutant CYP3A5*3. Correlation analysis revealed that ifosfamide N-dechloroethylation was significantly associated with CYP3A4 and CYP3A5 protein concentration but not with age, sex, or CYP2B6 protein concentration. In hepatic microsomes not expressing CYP3A5 protein, ifosfamide N-dechloroethylation was inhibited 53 to 61% and 0 to 3% by monoclonal antibodies specific for CYP3A4/5 or CYP2B6, respectively. Ifosfamide N-dechloroethylation was not detected in renal microsomes obtained from CYP3A5*3/*3 donors. In contrast, it was readily measurable in microsomes isolated from four kidneys of CYP3A5*1 carriers, which was almost completely inhibited by the CYP3A inhibitor ketoconazole. CYP2B6 protein could not be detected in this panel of human renal microsomes. In conclusion, CYP3A5*1 genotype is associated with higher rates of ifosfamide N-dechloroethylation in human liver and kidneys.

Antineoplastic Agents, Alkylating↗
PubMed1993

Ifosfamide, mesna, and nephrotoxicity in children.

PURPOSE: With the increasing use of ifosfamide in pediatric malignancies, nephrotoxicity has emerged as a potentially serious adverse effect, which may be dose-limiting or may cause severe chronic morbidity, including glomerular impairment and/or Fanconi's syndrome. The purpose of this review was (1) to improve the documentation of ifosfamide nephrotoxicity in children, and (2) to consider the possible causative role of ifosfamide metabolites. DESIGN: (1) A grading system was developed that allowed documentation of the nature and severity of published reports of ifosfamide-induced nephrotoxicity, and evaluation of patient and treatment-related risk factors. (2) The relationship between the pharmacology of ifosfamide/mesna and nephrotoxicity was investigated by examination of published data, especially that concerning the quantitative differences in the metabolism of ifosfamide and its nonnephrotoxic structural isomer, cyclophosphamide. RESULTS: (1) Examination of 16 published reports (with assessable data from 40 children) demonstrated that ifosfamide-induced nephrotoxicity was associated with a wide range of patient ages and ifosfamide cumulative doses given by different administration schedules. (2) Chloroacetaldehyde, a major metabolite of ifosfamide only, may be at least partly responsible for the renal toxicity of this drug. Although mesna may be capable of detoxifying the toxic metabolite(s), delivery to the renal tubule may not be sufficient to provide adequate protection of tubular glutathione from depletion by the metabolite(s), which results in a failure to prevent nephrotoxicity. CONCLUSION: Increased understanding of the interindividual variability in the extent and nature of ifosfamide metabolism, which may be a major determinant of susceptibility to renal damage, may lead to improved use of the drug with less nephrotoxicity.

Child↗
PubMed1989

Potentiation of ifosfamide toxicity by chlordiazepoxide, diazepam and oxazepam.

The effects of chlordiazepoxide, diazepam and oxazepam on the lethal toxicity and metabolic activation of ifosfamide were investigated in mice. Ifosfamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). The prior administration of chlordiazepoxide, diazepam or oxazepam enhanced the toxicity of ifosfamide (778 mg/kg, i.p.) during observation for 6 d after the administration of ifosfamide. In chlordiazepoxide-, diazepam- or oxazepam-treated mice, a higher concentration of active metabolite in the plasma after the administration of ifosfamide (200 or 600 mg/kg, i.p.) was observed as compared with that in mice treated with ifosfamide alone. On the other hand, chlordizepoxide, diazepam or oxazepam markedly enhanced the activity of ifosfamide oxidase in the liver microsomes. These results suggest that the potentiation of ifosfamide toxicity is due to stimulation of the metabolic activation of ifosfamide by chlordizepoxide, diazepam and oxazepam.

Animals↗
PubMedDate not supplied

Evaluation of ifosfamide for treatment of various canine neoplasms.

lfosfamide (3-[2-chloroethyl]-2[(2 chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) is an alkylating agent with a broad spectrum of antitumor activity. The efficacy and toxicity of ifosfamide were evaluated in 72 dogs with spontaneously occurring tumors. Forty dogs (56%) had lymphoma, 31 (43%) had sarcomas, and 1 had a metastatic carcinoma. Five dogs received ifosfamide at dosages <350 mg/m2 IV. Neither toxicity nor response were observed, and the remaining dogs received ifosfamide at 350 mg/m2 (n = 18) and 375 mg/m2 body surface area IV (n = 49). Saline diuresis and the thiol compound mesna were used to prevent urothelial toxicity. Fifty-two dogs had measurable tumors and could be evaluated for response. Complete responses were seen in 1 dog with metastatic leiomyosarcoma of the urinary bladder and in 1 dog with metastatic cutaneous hemangiosarcoma. One dog with lymphoma had a partial response for 112 days. Six dogs with splenic hemangiosarcoma received ifosfamide postsplenectomy and their median survival time was 147 days. The acute dose limiting toxicity was neutropenia 7 days after administration of ifosfamide. The median and mean neutrophil counts 7 days after ifosfamide at 350 mg/m2 were 2,035 cells/microL and 4,773 cells/microL, respectively (n = 12). The median and mean neutrophil counts 7 days after ifosfamide at 375 mg/m2 were 2,500 cells/microL and 3,594 cells/microL, respectively (n = 37). No dog developed clinical or microscopic evidence of hemorrhagic cystitis. Ifosfamide appears safe to use in tumor-bearing dogs, and the evaluation of combination chemotherapy protocols that include ifosfamide should be considered.

Animals↗
PubMed1994

Ifosfamide clinical pharmacokinetics.

This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide ('activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater antitumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy.

Administration, Oral↗
PubMed1999

The role of ifosfamide in the treatment of lymphomas.

Over the last few decades, progress has been made in classification and treatment guidelines for patients with lymphoma with differing prognostic factors. As investigators look for alternatives to current standard therapy there has been a resurgence of interest in the alkylating agent ifosfamide. A basic tenet of lymphoma therapy has been to use combinations of non-cross resistant agents in an effort to avoid tumor resistance. Ifosfamide is at least partially non-cross resistant with cyclophosphamide, and because it is often only modestly myelosuppressive, it is useful in combination regimens. Other toxicities of ifosfamide, including urinary bladder toxicity and neurotoxicity, are generally predictive and seldom occur in clinical practice with standard ifosfamide doses and proper screening and preventive therapy. Several regimens incorporating ifosfamide in a variety of doses and schedules have demonstrated clinical efficacy in the treatment of lymphomas. Ifosfamide is most commonly used in regimens for patients with relapsed or refractory disease, although there has been interest in ifosfamide as part of initial therapy regimens. Ifosfamide is an active agent as part of combination therapy for patients with both indolent and aggressive relapsed lymphomas, and has also been used in high-dose therapy regimens followed by stem cell or bone marrow rescue. Future studies incorporating ifosfamide should be directed towards its use in outpatient regimens as initial therapy for patients with lymphoma and in regimens designed for patients with relapsed or refractory disease.

Antineoplastic Agents, Alkylating↗
PubMed1999

Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children.

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. The authors sought to determine factors that predict the risk for the development and severity of ifosfamide-induced nephrotoxicity in children and to examine the long-term outcome of this complication. A total of 174 children who had received ifosfamide for various cancers were studied. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score (none, mild, moderate, severe). Patients were assessed 4 to 12 weeks after each ifosfamide course, 3 months after completion of chemotherapy, and 5 years later. Of 174 children, 72 (41.4%) developed tubular dysfunction, whereas only 11 (6.3%) demonstrated glomerular dysfunction; 40 (23.0%) demonstrated mild toxicity, 16 (9.2%) demonstrated moderate toxicity, and 16 (9.2%) developed severe nephrotoxicity. The four severity subgroups (none, mild, moderate, severe) received comparable doses/m2/cycle of ifosfamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild, or no nephrotoxicity (median age: 2.2, 7.0, 8.2, and 10.5 years, respectively; p < 0.001) and received significantly higher cumulative doses of ifosfamide (49.6 +/- 12.3, 46.0 +/- 13.1, 36.2 +/- 9.7, and 33.8 +/- 7.6 g/m2, respectively; p < 0.001). Cumulative doses of cisplatin were higher among children with severe nephrotoxicity compared to those with moderate, mild, or no toxicity, although this difference did not reach statistical significance. Of all risk factors analyzed by multiple regression analysis, age was the most significant predictor for the grade of nephrotoxicity (p < 0.001), followed by the cumulative dose of ifosfamide (p = 0.005). Seven out of 16 children (44.0%) with severe nephrotoxicity and 4 out of 16 children (25.0%) with moderate nephrotoxicity demonstrated severe chronic tubular toxicity over a follow-up period of 5 years. Since severe ifosfamide-induced renal toxicity tends to be chronic in a substantial number of treated children, it should be balanced carefully against efficacy. Cumulative ifosfamide doses of 45 g/m2 and above should be carefully considered, especially in children younger than age 3.

Adolescent↗
PubMed1993

[Ifosfamide-induced nephrotoxicity].

BACKGROUND: A number of acquired De-Toni-Debre-Fanconi-Syndromes have been reported after cytostatic treatment with Ifosfamide. For the majority of these patients prognosis of renal function was poor. In our study we evaluated the frequency of subclinical tubulopathies, the influence of the cumulative Ifosfamide dose and other risk factors and the prognosis of once established tubular dysfunction. METHODS: 79 patients after polychemotherapy regimens employing Ifosfamide (n = 39), Ifosfamide plus Cisplatinum (n = 35) or Cisplatinum (n = 5) were examined at least 3 months after completion of therapy. Beside the creatinine-clearance we evaluated glomerular and tubular function by measurement of transferrin, immunoglobuline G, Alpha-1-microglobuline and N-Acetyl-beta-D-Glucosamidaseexcretion and by tubular reabsorption of phosphate and aminoacids. RESULTS: Renal hyperaminoaciduria was found most often, and there was no linear correlation between the cumulative Ifosfamide-dose and phosphate reabsorption. A reduced glomerular filtration rate and glomerular proteinuria were found in about 10.5% of patients. Approximately half of the patients had tubular dysfunction. Impairment of phosphate reabsorption once established did not normalize in the majority of patients. Cisplatinum was found to worsen the Ifosfamide-induced tubulopathy. CONCLUSION: Our results indicate subclinical tubulopathy after Ifosfamide in a high proportion of patients. This Ifosfamide induced nephrotoxicity is worsened by Cisplatinum and seems to be irreversible for the majority of patients. To describe and to prevent Ifosfamide-induced nephrotoxicity, further studies should focus on: 1. the identification of the risk-groups/patients and additional risk factors, 2. the estimation of the prognosis of once established renal damage, 3. the clarification of the pathomechanism.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study.

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.

Adult↗
PubMed1997

Urinary proton magnetic resonance studies of early ifosfamide-induced nephrotoxicity and encephalopathy.

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.

Adult↗