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PubMed2001

Young age and the risk for ifosfamide-induced nephrotoxicity: a critical review of two opposing studies.

Ifosfamide has been in use as an effective antineoplastic agent for solid tumors in both children and adults since the late 1960s. Although some adverse effects (e.g. hemorrhagic cystitis) can be overcome by the co-administration of 2-mercaptoethanesulfonate (MESNA), others such as nephrotoxicity cannot. There is a consensus that factors such as the cumulative dose of ifosfamide and concomitant cisplatin administration may influence not only the incidence but also the severity of ifosfamide-induced renal toxicity. Several preliminary studies suggested young age as a risk factor for nephrotoxicity; however, there is little agreement on this. The reasons for this uncertainty may include sample size, study design, dose and differences in renal function assessment. In this review we examine the two largest cohort studies conducted in pediatric patients. One study suggests that ifosfamide-induced renal toxicity is age- related, whereas analysis of the other failed to show age as an important predictor for ifosfamide-induced renal toxicity. The studies differed in design, end-points of toxicity and concomitant drug therapy. Due to the effectiveness of ifosfamide as an antineoplastic agent, it is important that an understanding of the factors that predispose pediatric patients to ifosfamide-induced nephrotoxicity be obtained.

Aging↗
PubMed1999

Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5-150 microM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of chloroacetaldehyde. Ifosfamide (1000-10,000 microM) toxicity was detected only at concentrations of 4000 microM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity.

Acetaldehyde↗
PubMed1994

Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide.

Two NADPH-dependent metabolic routes for the anticancer drug ifosfamide, 4-hydroxylation (activation) and N-dechloroethylation (a detoxication pathway), were studied in human liver microsomes to identify the cytochrome P450 enzymes involved. Naringenin, a grapefruit aglycone and an inhibitor of cytochrome P450 3A4 (CYP3A4)-catalysed reactions, was found to inhibit ifosfamide activation and N-dechloroethylation by human liver microsomes. IC50 for both reactions was of the order of 70 microM. The CYP3A4-specific inhibitor triacetyloleandomycin inhibited ifosfamide N-dechloroethylation by human liver microsomes with an IC50 of approximately 10 microM. Furthermore, anti-human CYP3A4 antiserum inhibited by about 80% N-dechloroethylation of ifosfamide by human liver microsomes. The relative levels of cytochromes P450 1A, 2C, 2E and 3A4 in 12 human livers were determined by western blotting analysis. A strong correlation (P < 0.001) was observed between CYP3A4 expression and both activation and N-dechloroethylation of ifosfamide. A role for human CYP3A4 in both pathways of ifosfamide metabolism was thus demonstrated. This was substantiated by the observation that the nifedipine oxidase activities of the 12 samples of human liver microsomes correlated with ifosfamide activation (P < 0.009) and N-dechloroethylation (P < 0.001). These findings have important clinical implications. The involvement of the same key cytochrome P450 enzyme in both reactions prohibits selective inhibition of the N-dechloroethylation pathway, as might be desirable to reduce toxic side effects. They also demonstrate the need to consider interaction with co-administered drugs that are CYP3A4 substrates.

Antibodies↗
PubMed1990

Modulation of the control of mutagenic metabolites derived from cyclophosphamide and ifosfamide by stimulation of protein kinase A.

The phosphorylation of the 2 major phenobarbital-inducible cytochrome P450 isoenzymes IIB1 and IIB2 was increased in intact hepatocytes by the action of the membrane-permeating cAMP derivative N6,O2'-dibutyryl-cAMP. Under these conditions cyclophosphamide and ifosfamide (which are known to be activated by cytochrome P450 IIB1) were investigated for mutagenicity in Salmonella typhimurium TA1535 and TA100 and for cytotoxicity in TA1535. Cyclophosphamide and ifosfamide were transformed to mutagenic and cytotoxic metabolites by the hepatocytes. The activation of both drugs to mutagens was markedly reduced after pretreatment of the hepatocytes with the membrane-permeating cAMP derivative N6,O2'-dibutyryl-cAMP. Cyclophosphamide and ifosfamide activation were reduced to 51% and 38% of unstimulated controls respectively, when hepatocytes were incubated for 1 h with N6,O2'-dibutyryl-cAMP in the presence of the phosphodiesterase inhibitor theophylline, and Salmonella typhimurium TA1535 was used. A marked reduction in mutagenicity of cyclophosphamide (35% compared with unstimulated controls) was also observed under different experimental conditions, namely after pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP for 1.5 h without theophylline and using Salmonella typhimurium TA100 as target strain. Continued presence of the cytochrome P450 IIB1 and P450 IIB2 inducer phenobarbital in the stimulation medium increased the mutagenicity of cyclophosphamide and led to an even more marked reduction of mutagenicity by pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP and theophylline. In order to investigate whether the observed changes were metabolism-related, the ifosfamide metabolite ifosfamide mustard which does not require metabolic activation by cytochrome P450 was studied under the same conditions. Its mutagenicity was indistinguishable after incubation with N6,O2'-dibutyryl-cAMP-treated or with unstimulated hepatocytes. Also the metabolic formation of cytotoxic metabolites from cyclophosphamide and ifosfamide but not that of ifosfamide mustard was markedly decreased by pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP and theophylline. Thus the stimulation of protein kinase A in intact cells has important consequences for the control of genotoxic and cytotoxic metabolites and represents a fast and short-term regulation of it.

Animals↗
PubMed1994

Enantiomeric separation of R- and S-ifosfamide and their determination in serum from clinical subjects.

A method to measure racemic, R- and S-ifosfamide concentrations from the serum of patients receiving ifosfamide chemotherapy has been developed. The racemic ifosfamide concentrations are quantified on a separate system and then the ratio of the enantiomers is determined using an achiral-chiral coupled system. Racemic ifosfamide is separated on the achiral system using a C1 spherisorb stationary phase and the eluent containing analyte is selectively transferred to the chiral system for separation of the two enantiomers by an alpha 1 glycoprotein column. On both systems the mobile phase is 1% acetonitrite in 0.015 M phosphate buffer (pH 4) at a flow-rate of 1 ml/min. The retention times of S- and R-ifosfamide were 11.6 and 13.0 mins, respectively, with a resolution factor of 1.53. Serum concentrations at least three to four half-lives post-infusion were detected by this method. In ten patients, following a mean +/- S.D. 1-h infusion of 3.9 +/- 0.32 g racemic ifosfamide, the mean +/- S.D. clearances of R- and S-ifosfamide were 0.061 +/- 0.013 and 0.072 +/- 0.014 1 h-1 kg-1.

Aged↗
PubMed2004

Renal ontogeny of ifosfamide nephrotoxicity.

Ifosfamide-induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity induced by ifosfamide, with younger children (<3 years) substantially more vulnerable. The mechanisms leading to this age-related ifosfamide-induced renal damage have not been identified. Underlying this work is the hypothesis that renal ontogeny is involved in the expression and activity of the cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. We evaluated renal CYP3A and 2B22 activity in pigs between the ages of 1 day and adulthood, as well as the metabolism of ifosfamide by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF, respectively). Kidney CYP3A messenger RNA expression peaked 15 to 60 days (0.7-76 +/- 0.19 CYP3A/actin ratio; P < 0.001). Subsequently, this level decreased to adult values (0.54 - 0.03 CYP3A/actin ratio; P = 0.04). Similarly, we detected an increase in the ifosfamide-metabolism rate between young (18 +/- 2 pmol/mg protein/min) and adult (12.2 +/- 0.17 pmol/mg protein/min) animals (P = 0.002). Ours is the first documentation of ontogeny of renal CYP3A and of renal ifosfamide metabolism. These data suggest that age-dependent ifosfamide nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde.

Acetaldehyde↗
PubMedDate not supplied

Effects of subchronic ifosfamide-mesna treatment on testes and semen characteristics in the rabbit.

Ifosfamide, a chemotherapeutic agent with a broad spectrum of antineoplastic activity, is concurrently administered with the uroprotectant mesna to avoid the urotoxic effect. This study was undertaken to investigate possible effects of ifosfamide-mesna treatment on the testes and semen characteristics in rabbits. Sexually mature New Zealand White male rabbits received intravenously 10 weekly treatments of ifosfamide+mesna (groups A, B and C received 30, 45 or 60 mg/kg of body weight ifosfamide+6, 9 or 12 mg/kg of body weight mesna, respectively, followed by a second equal dose of mesna 4 h later); groups MA, MB and MC received mesna alone at corresponding doses; and group S received normal saline. Reproductive organ weight as well as various qualitative and quantitative parameters of testis histology (minor diameter of seminiferous tubules, the most advanced germ cell type in seminiferous tubule identified in cross sections, and the number of germ cells per stage 1 seminiferous tubule cross section) were determined 1 day and 20 weeks after the treatment period, while semen quality (sperm count, sperm morphology and sperm progressive motility) and libido were evaluated on a weekly basis. Changes were noted only in the ifosfamide+mesna treated animals. One day after treatment, reproductive organ weights were decreased in groups A-C. Major histopathological lesions were not found; however, quantitative histological endpoints were altered in groups A-C. Transient oligospermia and teratozoospermia were noted in groups B and C, while asthenozoospermia was observed in group C only. The time course of these sperm alterations suggested possible bioaccumulation and residual activity of ifosfamide. Libido remained normal. The decrease in reproductive organ weights persisted in groups B and C to 20 weeks after treatment but only one quantitative histological endpoint, the number of the round spermatids per stage 1 seminiferous tubule cross section, remained decreased in group C. These results suggest that subchronic treatment with ifosfamide-mesna suppressed spermatogenesis and epididymal sperm maturation in the rabbit. Germinal epithelium recovery was not complete because although sperm characteristics returned to pretreatment values, not all histological alterations were ameliorated.

Animals↗
PubMed1997

Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas.

BACKGROUND: Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS. PATIENTS AND METHODS: Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m2/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 micrograms/m2/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting. RESULTS: A total of 159 cycles of therapy were given (median 4 per patient, range 3-6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5-21+ months), and the overall median survival ranged from 6-30+ months (median 13 months). CONCLUSIONS: High-dose ifosfamide is an active regimen in anthracycline-pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.

Adult↗
PubMed1999

Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti-tumor activity in patients with metastatic breast cancer.

For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 microg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6x10(6) CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10-13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs. ifosfamide-paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0x10(6)/kg per day during days 9-14. After a median of 3 (range 1-5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2x10(6)/kg (range 0.16-54.9), 37x10(4)/kg (range 5.7-247) and 7.3x10(8)/kg (range 2.1-26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity.

Adult↗
PubMed1992

Use of ifosfamide in the management of breast cancer.

Ifosfamide, a cytostatic drug highly active in vivo, has slight superiority over cyclophosphamide. It proved effective in experimental tumor systems including the C3H mammary carcinoma. Clinical studies of ifosfamide as monotherapy in breast cancer, begun in 1974 by Ahmann et al., reported a 20% objective response. Subsequent trials were conducted from 1974 through 1977 using ifosfamide as monotherapy, and ifosfamide was also combined with other chemotherapeutic agents. In 1975, Hartwich and coworkers used the combination ifosfamide/vincristine with a 25% overall response. With the introduction of the uroprotector mesna, more studies were instituted. In 1984, using the IMF combination (ifosfamide/methotrexate/5-fluorouracil), we reported a 25% overall response. Other groups also reported good results for ifosfamide-containing combinations, with overall responses ranging from 25% to 79%. Recently, Sanchiz and Milla used high-dose ifosfamide to treat metastatic breast cancer, with a 40% overall response. In conclusion, ifosfamide's efficacy in breast cancer has been confirmed and the drug is highly recommended in combination chemotherapy as a first-line treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Phase I study of paclitaxel (Taxol) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer. A study of the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Paclitaxel (Taxol) and ifosfamide are among the most active single agents for the treatment of non-small-cell lung cancer. We undertook this phase I dose escalation study to determine the maximum tolerated doses of these drugs which could be administered without growth factors to untreated patients with tumours of this type. PATIENTS AND METHODS: Forty patients with advanced non-small-cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide every 3 weeks. Groups of 3 patients were entered at escalating dose levels in traditional phase I design. Starting doses were paclitaxel, 100 mg/m2, and ifosfamide 3 g/m2, and all patients received premedication with dexamethasone, diphenhydramine and a 5-HT3 blocker. Dose escalation occurred only after full toxicity assessment for 2 cycles for all patients in the dose level. RESULTS: Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neuro-toxicity above this level. Instead, ifosfamide was increased to 4 g/m2 for the final level. At these doses, dose-limiting myelosuppression was not seen, and there was only 1 episode of febrile neutropenia in 164 treatment cycles. Drug-related toxicities of ifosfamide included gross hematuria and confusion in 1 patient each, and paclitaxel-related symptoms included flu-like syndrome in most patients, mild to moderate arthralgia and/or myalgia in 8 and 25 patients, respectively, parasthesiae in 15 patients and mild to moderate hypersensitivity reactions in 15 patients each. Partial response was seen in 20.5% of patients (CI 9.3%-36.5%). SUMMARY: Out-patient paclitaxel given over 3 hours and single-dose ifosfamide over 1 hour may be combined safely without the need for hematopoietic growth factors for the treatment of patients with non-small-cell lung cancer. The recommended doses for phase II study are paclitaxel, 225 mg/m2 and ifosfamide, 4 g/m2 every 3 weeks.

Adult↗
PubMed2005

Evaluating risk factors for the development of ifosfamide encephalopathy.

BACKGROUND: Ifosfamide is an important part of chemotherapeutic regimens used to treat a variety of malignancies. One potential side effect of the drug is encephalopathy, which may manifest itself as a variety of symptoms, ranging from agitation to seizures and coma. The goal of this review is to identify the prevalence of ifosfamide encephalopathy at Barnes-Jewish Hospital from 1995 to 2003, and to identify risk factors associated with the condition. METHODS: A retrospective cohort study of all patients receiving ifosfamide at Barnes-Jewish Hospital in St. Louis, Missouri, from late 1995 to early 2003 was performed. In sum, the authors reviewed chemotherapy administrations for a total of 237 individual patients. Patients were divided into control subjects and cases of encephalopathy. RESULTS: A total of 237 patients received ifosfamide during the study period. Thirty-eight patients (16%) underwent chemotherapy rounds during which encephalopathy occurred. Serum albumin was significantly lower in the case population (3.3 g/dL) compared with the control population (3.7 g/dL). The odds ratio of hypoalbuminemia for the development of encephalopathy was calculated as 4.3 (CI, 2.26-8.3). The average creatinine values were in the normal range for both groups, although slightly higher in the case population with statistical significance. Age and ifosfamide dose were not significantly different between the 2 groups. The most common manifestation of encephalopathy was confusion. Methylene blue, which has been thought to reverse the condition, was administered in 26 cases. CONCLUSION: The prevalence of ifosfamide encephalopathy during the study period was 16%. Albumin was significantly lower among those patients who experienced encephalopathy, whereas age, creatinine, and ifosfamide dose were not significantly different between the 2 groups.

Adult↗
PubMed1995

Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma.

Ifosfamide is a chiral pro-drug which is administered clinically in its racemic form. Serum concentrations of rac-ifosfamide and its enantiomers were measured in 12 patients with lung carcinoma following a mean (+/- s.d.) intravenous dose of 4.2 (0.83) g infused over 1 h. The mean (+/- s.d.) volumes of distribution (VSS) of rac, (R)- and (S)-ifosfamide were 0.61 (0.17), 0.60 (0.16) and 0.61 (0.19) l kg-1, respectively. The mean (+/- s.d.) half-lives and clearances were 6.57 (1.69), 7.12 (1.92) and 5.98 (1.52) h and 0.065 (0.013), 0.060 (0.013) and 0.072 (0.014) l h-1 kg-1 for rac, (R)- and (S)-ifosfamide, respectively. The half-life of (S)-ifosfamide was significantly (P < 0.001) shorter than that of (R)-ifosfamide and it had a significantly higher clearance (P < 0.001). There was no significant difference in the volumes of distribution of the enantiomers. The clinical significance of the faster elimination of (S)-ifosfamide is not known.

Aged↗
PubMed1999

Ifosfamide-induced stomatocytosis and mesna-induced echinocytosis: influence on biorheological properties of blood.

Ifosfamide is an alkylating agent which has poorly understood toxic side effects such as encephalopathy. We hypothesized that ifosfamide and concomitantly applied mesna could have an influence on the flow properties of blood, and thus carried out an in vitro study. Whole blood was incubated in vitro with increasing concentrations of ifosfamide (0-50 mg/ml), mesna (0-20 mg/ml) and combinations thereof. Chloroacetaldehyde, a major metabolite of ifosfamide, was also studied (0-5 mmol/l). Ifosfamide led to a dose-dependent stomatocytic shape transformation and mesna to an echinocytic shape transformation of erythrocytes. These shape changes were reversible upon removal of the causing agent. Both shape changes increased whole blood viscosity. Erythrocyte aggregation was decreased by both drugs at high concentration. Erythrocyte deformability, as measured with the transit time through 5-microm pores, was decreased by mesna and remained unaffected by ifosfamide. These effects were seen at concentrations which may be reached in vivo at the infusion site of the drugs into a vein and in the urinary tract. We conclude that ifosfamide and mesna interact with the lipid bilayer of the cell membrane, which may contribute to the toxicity of the compounds.

Adult↗
PubMed1988

Ifosfamide and mesna: marginally active in patients with advanced carcinoma of the pancreas.

Ifosfamide, an analogue of cyclophosphamide, has therapeutic activity against a wide variety of human malignancies. In a phase II trial in carcinoma of the pancreas, we treated 31 patients who had not received prior chemotherapy with a median ifosfamide dose of 2 g/m2/d (range, 1.5 to 2 g/m2/d) administered intravenously (IV) over one hour for five consecutive days every 3 weeks. 2-mercaptoethane sulphonate (mesna), an acrolein antagonist with known uroendothelial protective properties, was administered IV at a dose of 400 mg/m2 over 15 minutes before the daily dose of ifosfamide and repeated every four hours for two additional doses. Among 30 evaluable patients, one patient achieved a complete remission (26+ months) and another patient had a partial remission (4 months). The median duration of survival of all patients from the start of ifosfamide therapy was only 3 months (range, 1 to 26+ months). Treatments were generally well tolerated. The most common toxic effects included granulocytopenia, nausea and vomiting, malaise, anorexia, and mild hematuria. Mesna offers an adequate protection against uroendothelial injury caused by ifosfamide. Despite the previously reported response rate of greater than 20% at the same or lower doses of ifosfamide in other studies, our data suggest that ifosfamide is only marginally active against cancer of the pancreas and appears to be of minimal value in the treatment of patients with this tumor.

Adult↗
PubMed1994

Unilateral nephrectomy and cisplatin as risk factors of ifosfamide-induced nephrotoxicity: analysis of 120 patients.

PURPOSE: This study was performed to identify risk factors of ifosfamide-induced renal damage. PATIENTS AND METHODS: Renal function was assessed in 120 patients at a minimum of 3 months after completion of chemotherapy including ifosfamide. The cumulative ifosfamide dose ranged from 2 to 95 g/m2 (median, 30 g/m2). Ten patients had undergone unilateral nephrectomy; combination cytostatic treatment included cisplatin in 51 and methotrexate in 57. Sixty-eight patients had received gentamicin treatment. The glomerular filtration rate was estimated using the Schwartz formula. Proximal tubular function was assessed by the percent reabsorptions of glucose and 16 amino acids, the fractional excretion of sodium, and the fractional reabsorption of phosphate. In addition, the serum bicarbonate level was measured. RESULTS: Proximal tubular dysfunction--with a predominance of renal amino acid (66.3%) and phosphate loss (38.3%)--was much more frequent than both glomerular impairment and acidosis. Seven patients were identified as having renal Fanconi's syndrome, and generalized tubulopathy was noted in another 15 patients. Ifosfamide-induced nephrotoxicity was dose-dependent, with a weak linear inverse correlation between cumulative ifosfamide dose and fractional phosphate reabsorption. Unilateral nephrectomy proved to be the single most important risk factor (odds ratio for the development of renal Fanconi's syndrome, 11.4), but cisplatin also significantly enhanced ifosfamide-mediated nephrotoxicity. Methotrexate, gentamicin, and patient age at primary diagnosis had no influence on renal function. CONCLUSION: Ifosfamide chemotherapy should probably be restricted in patients after unilateral nephrectomy.

Adolescent↗
PubMed1998

Pharmacokinetics of an intravenous-oral versus intravenous-mesna regimen in lung cancer patients receiving ifosfamide.

PURPOSE: To compare the pharmacokinetics of the approved I.V. (intravenous) mesna regimen and an investigational I.V.-oral regimen that could be used in outpatients who receive ifosfamide. PATIENTS AND METHODS: The I.V. regimen consisted of three I.V. mesna doses given at 0, 4, and 8 hours after ifosfamide administration. The investigational regimen included an I.V. mesna dose given concurrently with ifosfamide, followed 2 and 8 hours later by oral administration of mesna tablets. I.V. and oral mesna doses equaled 20% and 40%, respectively, of the ifosfamide dose. The study subjects were 12 lung cancer patients who received ifosfamide 1.2 g/m2 daily for 5 days. The patients were randomized to receive either the I.V.-oral or I.V. mesna regimen on day 1, followed by crossover to the other regimen on days 2 through 5 of ifosfamide treatment. The urinary profiles of mesna and dimesna excretion were determined on days 1, 2, and 5; pharmacokinetic parameters for blood samples were determined only on day 5. RESULTS: During the first 12 hours after ifosfamide administration, the amount of mesna excreted and the profile of urinary mesna excretion was similar for both regimens; however, the I.V.-oral regimen showed less fluctuation in the excretion rate and higher trough values. During hours 12 to 24, about eightfold more mesna was excreted by patients given the I.V.-oral than the I.V. regimen. CONCLUSION: These pharmacokinetic data show that the I.V.-oral regimen should be at least as uroprotective as the I.V. mesna regimen. Patients may also benefit from the I.V.-oral regimen because of the higher trough values during hours 0 through 12 and the sustained urinary mesna excretion during hours 12 through 24.

Administration, Oral↗
PubMed2005

Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.

PURPOSE: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Acetylmuramyl-Alanyl-Isoglutamine↗