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PubMed1994

Biological monitoring of cyclophosphamide and ifosfamide in urine of hospital personnel occupationally exposed to cytostatic drugs.

The occupational exposure of 21 nurses and pharmacy personnel from eight hospitals to cyclophosphamide and ifosfamide was determined by quantifying the amount of the drugs handled and by measuring the urinary excretion of the unmetabolised substances. Preparing antineoplastic drugs for intravenous treatment was the major task of all study participants. Twenty four hour urine was collected on days when cyclophosphamide and/or ifosfamide were mixed, on average 3900 mg cyclophosphamide and/or 5900 mg ifosfamide. The analyses were performed by gas chromatography with electron capture, detection limit 2.5 micrograms/24 hour urine. Despite standard safety precautions, including a vertical laminar air flow safety cabinet and gloves, cyclophosphamide was detected in 12 of 31 and ifosfamide in four of 21 urine samples on days when the drugs were handled. Excretion of cyclophosphamide ranged from 3.5 to 38 micrograms/24 h (mean 11.4 micrograms/24 h) urine, ifosfamide from 5 to 12.7 micrograms/24 h (mean 9 micrograms/24 h) urine. Based on an excretion rate of 11.3% unmetabolised cyclophosphamide, the average amount excreted corresponded to an uptake of 101 micrograms cyclophosphamide. For ifosfamide the mean quantity incorporated was 20 micrograms assuming that 45% of the drug was excreted. Pertaining to the doses handled, the uptake of cyclophosphamide and ifosfamide was estimated to be approximately 0.0025% and 0.0004% respectively. Despite time-consuming purification procedures, gas chromatographic analysis is a suitable method for monitoring personnel occupationally exposed to cyclophosphamide and ifosfamide and is a major contribution to the evaluation of potential health risks of exposed personnel.

Adult↗
PubMedDate not supplied

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study.

BACKGROUND: While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated patients, the majority of individuals with advanced disease ultimately relapse. Paclitaxel, a new and novel antimicrotubule agent, has shown activity as a salvage therapy in epithelial ovarian cancer. More importantly, in a prior study, it has been shown to be active in tumors that have displayed resistance to platinum compounds, with a reported response rate of 20%. Ifosfamide has shown activity in the treatment of patients who previously demonstrated clinical resistance to a platinum-cyclophosphamide combination. Recently, a synergistic activity of Taxol combined with ifosfamide has been reported in ovarian cell lines. Based on these data, a phase I/II study of a combination treatment with paclitaxel and ifosfamide was performed. PATIENTS AND METHODS: Thirty-one patients with recurrent ovarian cancer or ovarian cancer refractory to cisplatin (CDDP)-containing regimens were treated with paclitaxel at a dose of 135 mg/m2 on day 1; ifosfamide was administered at 1 g/m2 on days 2 and 3 for the first cycle and 1.5 and 2 g/m2 with the same schedule in cycles 2 and 3, respectively. In the absence of toxicity, the dose of ifosfamide was maintained at 2 g/m2 for the last three cycles. Cytotoxic therapy was repeated every 3 weeks. RESULTS: A 30% overall objective response rate was achieved in the 30 patients assessable for response. Among 21 platinum-resistant patients, 4 partial responses (19%) were observed, while in the 9 platinum-sensitive patients 2 complete responses and 3 partial responses (55%) were observed. Myelosuppression was the predominant toxicity. Leukopenia (WHO grade 3-4) occurred in 10% of patients who received ifosfamide at a dose of 1 g/m2 and in 18% of patients treated with ifosfamide at 1.5 g/m2. CONCLUSION: Our results confirmed a low activity of paclitaxel in platinum-resistant patients. The results of this combination treatment with paclitaxel-ifosfamide in our platinum-sensitive patients support further investigations in a randomized study of the combination regimen against paclitaxel alone or retreatment with organoplatinum compounds.

Aged↗
PubMed1998

Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors.

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. Many risk factors have been proposed to play a role in the development and severity of nephrotoxicity in children receiving ifosfamide, among which are 1) patient's age, 2) cumulative ifosfamide dose, 3) concurrent administration of cis or carboplatinum, 4) unilateral nephrectomy, and 5) method of ifosfamide administration. However, presently there is no consensus regarding the weight of each one of them. Therefore, we critically reviewed the major studies that have evaluated the different risk factors in an attempt to determine the relative importance of each. Cumulative ifosfamide doses of >/=60 g/m appears to be the most consistent independent predictor for both the development and the severity of nephrotoxicity, whereas a younger age (<5 years of age) was associated primarily with the more severe and chronic forms of proximal tubulopathy. Comparable incidence and severity forms of proximal tubulopathy among children who had been treated with cis platinum in addition to ifosfamide and those who had not indicate that platinums probably potentiate ifosfamide-induced renal damage rather than act as a major independent risk factor. Finally, although unilateral nephrectomy has been proposed as a significant risk factor in different studies, the relatively small number of nephrectomized children in these cohorts limit the strength of this association. To reduce the frequency and severity of ifosfamide-induced nephrotoxicity, it appears that cumulative doses of 60 g/m should be considered carefully, especially in children <5 years of age.

Adolescent↗
PubMed2006

Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas.

OBJECTIVE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of ifosfamide in tumor-bearing cats. ANIMALS: 38 cats with resected, recurrent, or metastatic sarcomas. PROCEDURE: The starting dosage of ifosfamide was 400 mg/m(2) of body surface area, IV, and dosages were increased by 50 to 100 mg/m(2) in cohorts of 3 cats. To protect against urotoxicosis, mesna was administered at a dosage equal to 20% of the calculated ifosfamide dosage. Diuresis with saline (0.9% NaCl) solution before and after administration of ifosfamide was used to minimize nephrotoxicosis. Samples for pharmacokinetic analysis were obtained after the MTD was reached. RESULTS: 38 cats were entered into this phase I study and were administered a single dose of ifosfamide at various dosages. The MTD was 1,000 mg/m(2), and neutropenia was the DLT. Seven of 8 episodes of neutropenia were on day 7 after treatment, and 1 cat developed severe neutropenia on day 5. Adverse effects on the gastrointestinal tract were generally mild and self-limiting, the most common of which was nausea during ifosfamide infusion. One cat had signs consistent with a drug-induced hypersensitivity reaction. There were no episodes of hemorrhagic cystitis or nephrotoxicosis. Correlations between pharmacokinetic variables and ifosfamide-associated toxicoses were not found. Preliminary evidence of antitumor activity was observed in 6 of 27 cats with measurable tumors. CONCLUSIONS AND CLINICAL RELEVANCE: The dosage of ifosfamide recommended to treat tumor-bearing cats is 900 mg/m(2) every 3 weeks. This dosage should be used in phase II clinical trials.

Animals↗
PubMed2001

The role of ifosfamide in the treatment of relapsed and refractory lymphoma.

Ifosfamide is an alkylating agent with proven efficacy in the treatment of solid tumours and malignant lymphomas. Because it causes only mild to moderate myelosuppression, ifosfamide is often used in combination regimens with other agents. Ifosfamide has been mainly used in therapy of lymphoma as a component of salvage regimens, but high-dose ifosfamide is also effective in the mobilization of peripheral stem cells for treatment of patients with relapsed or refractory lymphoma with regimens containing autologous stem cell transplantation. Based on promising data with a new combination regimen containing idarubicin, etoposide and ifosfamide (IIVP-16) in patients with poor-risk non-Hodgkin's lymphoma, we have performed a phase II study using DIZE (dexamethasone 20 mg i.v. days 1-4, idarubicin 8 mg/m2 i.v. days 1 + 2, ifosfamide 1.0 g/m2 continuous infusion (c.i.) days 1-4, and etoposide 160 mg/m2 c.i. days 1-4) in patients with relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma. In 43 evaluable patients, the response rate was 58%, including 11 complete remissions (CR) and 14 partial remissions (PR). The mean duration of response was 8 months (1-30). Myelosuppression was generally mild with mean duration of neutropenia < 1000/microL of 2.5 days (range 0-18) and thrombocytopenia < 25,000/microL of 1.5 days (0-17). Thus, DIZE is an effective and safe regimen for pretreated patients with aggressive lymphoma. These results appear to compare favourably with other salvage regimens such as IMVP-16 or DHAP. In conclusion, salvage regimens containing ifosfamide can play an important role in patients who are not eligible for high-dose chemotherapies. Moreover, ifosfamide might also have a role in reducing tumour burden and selecting those patients who qualify for HDCT.

Antineoplastic Agents, Alkylating↗
PubMed2003

Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide.

PURPOSE: We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma. EXPERIMENTAL DESIGN: Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days. RESULTS: Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response. CONCLUSION: On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care.

Administration, Oral↗
PubMedDate not supplied

[Nephrotoxicity of ifosfamide with special reference to Fanconi Syndrome].

UNLABELLED: The article is a case presentation of Fanconi syndrome in a patient treated with high doses of ifosfamide. ifosfamide nephrotoxicity relates to glomerular and tubular disfunction. Tubular disfunction type 2 (Fanconi Syndrome) is observed most often. In this syndrome hypophosphatemia, hyperphosphaturia, glucosuria, polyuria, aminoaciduria, hypokalemia and tubular acidosis are present. The treatment consists of electrolyte supplementation and acidosis reduction. Nephrotoxicity risk factors are: total ifosfamide doses and age under 3 years. Early diagnosis is possible by estimating b2 microglobulin and retinal binding protein. Normally used parameters of renal function are insufficient. MATERIAL AND METHODS: case report - N. W - 13-year-old patient with a skin's tumour was treated in our clinic. Euro Ewing-99 protocol with 100.8 g/m2 of ifosfamide was applied for 18 months. During treatment serum electrolytes, urea, creatinine and creatinine clearance were normal. 6 months after treatment a metastasis in the lung was detected. RESULTS: Fanconi Syndrome symptoms were noticed before introduction of chemotherapy. After treatment with small doses of ifosfamide (4.5 g/m2) the disorders became severe. For this reason, nephrotoxic cytostatics were excluded from further treatment, decreasing its efficiency. CONCLUSIONS: 1. Renal complications of ifosfamide may appear after treatment completion. Monitoring of renal function parameters is necessary during and after treatment. 2. When protocols with cyclophosphamide (less nephrotoxic than ifosfamide) prove to be of similar efficiency, this treatment could be an alternative for patients' with renal disfunction. 3. Patients with completed ifosfamide treatment shall be qualified for repeated chemotherapy carefully due to high-risk of renal disfunction.

Acute Kidney Injury↗
PubMed1989

The role of ifosfamide in testicular cancer.

Ifosfamide is one of the most active agents in testicular cancer, with a single-agent activity of 66% in untreated and 21% in cisplatin-pretreated patients. The antitumor effect is comparable in nonseminoma and seminoma. The 23% complete response (CR) rate in patients not pretreated with cisplatin is lower than for those pretreated with cisplatin. This indicates that ifosfamide is less active than cisplatin, and more active than bleomycin, the vinca alkaloids, and possibly etoposide. Ifosfamide and cisplatin are not cross-resistant, with a 67% response rate for cisplatin in ifosfamide-pretreated patients. In a prospective, randomized trial with 203 patients from 1978 to 1982, no significant survival advantage could be seen for PVB (cisplatin, vinblastine, bleomycin) plus ifosfamide v PVB after a 10-year follow-up. In patients refractory to or progressing with cisplatin treatment, ifosfamide-containing regimens rarely induce either partial responses (PRs) or CR. However, in patients relapsing or progressing after a favorable response to cisplatin-based chemotherapy, ifosfamide seems to potentiate the activity of cisplatin and etoposide therapy with about 30% CRs and 15% to 20% long-term, disease-free survivors. This can be explained by the synergism demonstrated in preclinical trials among these three drugs. Due to this high activity in relapsing patients, the cisplatin-etoposide-ifosfamide combination is currently being investigated as first-line treatment in poor risk testicular cancer patients. The optimal dose and schedule still have to be determined, particularly in the combination with granulocyte-granulocyte-macrophage colony stimulating factors that may allow dose escalation of these drugs. An important result of the 15-year follow-up of ifosamide in first-line treatment is the absence of late organ toxicity and particularly of secondary malignancies (1/331 patients) in this young patient population.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Ifosfamide in the treatment of soft-tissue sarcomas: experience at the West German Tumor Center, Essen.

The response of ifosfamide-based chemotherapeutic regimens was retrospectively analyzed in adult patients with advanced soft-tissue sarcoma who were treated at the West German Tumor Center, Essen, between 1978 and 1990. Single-agent ifosfamide was given either in split doses of 60-80 mg/kg by 4-h infusion over 5 days or as a continuous 24-h infusion of 5 g/m2. Ifosfamide was given either in split doses of 40-50 mg/kg over 5 days or as a continuous infusion of 5 g/m2 in combination with doxorubicin (40-60 mg/m2, day 1), cisplatin (20 mg/m2, days 1-5), or etoposide (100 mg/m2, days 1, 3, and 5). Mesna was given to all patients as prophylaxis against urotoxicity. Of 54 evaluable patients receiving single-agent ifosfamide, 5 achieved a complete response (CR) and 10 showed a partial response (PR), for an overall response rate of 28%. Objective responses were more frequent in previously untreated patients (47%) than in pretreated patients (15%; P < 0.01). The addition of doxorubicin (n = 41) or cisplatin (n = 29) to ifosfamide did not significantly increase the response rate (29% and 41%, respectively) or median duration of remission as compared with ifosfamide alone. In addition, no significant difference was observed between the two ifosfamide regimens used: the 24-h continuous-infusion schedule (5 g/m2 per course, 27% response rate) and the 5-day fractionated regimen (10-15 g/m2 per course, 19% response rate). We conclude that the response and the median duration of remission produced by single-agent ifosfamide compare favorably with the results achieved using single-agent doxorubicin and the usually more toxic combination regimens.

Adolescent↗
PubMed1995

Effect of ifosfamide treatment on glutathione and glutathione conjugation activity in patients with advanced cancers.

Several studies have suggested that the glutathione/glutathione S-transferase (GSH/GST) system is involved in resistance of tumors toward ifosfamide and other cytostatic agents. Besides, ifosfamide metabolites (in vitro) as well as ifosfamide treatment (in vivo) have been shown to decrease cellular GSH availability. In the present study, the in vivo effects of three different ifosfamide treatment schedules on the GSH/GST system were studied in patients with advanced cancers (n = 24): continuous i.v. infusions of 1300 mg/m2 daily for 10 days and 5000 mg/m2/day for 24 h, as well as a 4-h infusion of 3000 mg/m2 daily for 3 days. The GSH/GST system was characterized by administering bromisoval, a probe drug to assess GSH conjugation activity in vivo, as well as by daily monitoring of GSH concentrations in blood cells and plasma. Bromisoval pharmacokinetics was assessed before and at the end of the ifosfamide treatment. Blood cell GSH levels decreased significantly (P < 0.05) during the 3- and 10-day ifosfamide treatment schedules; the 24-h treatment had no effect. The ifosfamide treatment schedules had only minimal effects on bromisoval pharmacokinetics. Assuming that the kinetics of the probe drug provide an accurate reflection of enzyme activity, this suggests that GST activity remains unchanged. Because GSH conjugation of bromisoval enantiomers requires both GST activity and GSH availability, these results also indicate that, despite the 35% decrease in GSH in blood cells of two patient groups, the GSH availability of the cancer patients was not rate-limiting for GSH conjugation of bromisoval enantiomers. If GSH levels in blood cells reflect those in tumors/other tissues, the present results indicate that ifosfamide may be used clinically to decrease GSH levels. However, whether a 35% decrease is sufficient to increase tumor sensitivity toward (other) cytostatics remains uncertain.

Adult↗
PubMed1995

Etoposide, ifosfamide, and cisplatin therapy for refractory childhood solid tumors. Response and toxicity.

BACKGROUND: Etoposide, ifosfamide, and cisplatin (VIP) are each active in treating pediatric solid tumors, and this combination has been shown to be effective in treating adult germ cell tumors. Etoposide, ifosfamide, and cisplatin therapy was used to treat 11 patients, with ages ranging from 14 months to 22 years, with relapsed sarcoma, Wilm's tumor, and hepatoblastoma. METHODS: Etoposide, ifosfamide, and cisplatin therapy was administered daily for 3 days in doses of cisplatin 20 mg/m2 with mannitol 10 g/m2 for 1 hour, etoposide 100 mg/m2, and ifosfamide 1.5 g/m2 with MESNA 360 mg/m2 x 3 doses. A total of 65 courses (range, 3-10/patient) were administered, with 86% of the courses administered at full dose. Hematopoietic growth factors were not used. RESULTS: All 10 evaluable patients responded. Six patients had a complete response (CR) by computed tomographic or magnetic resonance imaging scan after one to three courses. The remaining four patients had a partial response (PR) (> 50% decrease in disease). One PR was converted to a CR by resection of the residual lesions. The major toxicity was myelosuppression. The median nadirs after full doses were as follows: leukocyte count of 900/mm3, absolute neutrophil count (ANC) of 156/mm3, platelet count of 61,000/mm3, and hemoglobin count of 8.6 g/dl; 75% of full dose courses led to an ANC of less than 500. Fever and neutropenia were observed after 8/55 (15%) full dose courses. Two episodes of bacteremia were noted, one with Staphylococcus epidermidis after full recovery of counts. The median time to hematologic recovery was 21 days (range, 14-29 days). No patient developed a decreased creatinine clearance level during therapy. Significant renal solute losses were observed in two patients, both of whom had been pretreated heavily with ifosfamide and had losses before VIP therapy. CONCLUSIONS: Etoposide, ifosfamide, and cisplatin appear to be active in treating childhood solid tumors. This therapy has predictable and tolerable myelotoxicity, and nephrotoxicity does not appear to be more severe than that observed after treatment with ifosfamide alone.

Adolescent↗
PubMedDate not supplied

Nephrotoxicity of ifosfamide in rats.

Renal proximal tubule cell injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. We investigated the effect of this medication on kidney function in rats. Animals received either 40 or 80 mg kg(-1) ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four treatment courses. Ifosfamide-treated rats had significantly lower body weight and hematocrit than sterile water-treated control rats. Animals receiving 40 mg kg(-1) ifosfamide developed isolated phosphaturia after their fourth and final treatment course. Rats receiving 80 mg kg(-1) ifosfamide had low-grade glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate, creatinine clearance, urinary sodium and potassium excretion and kidney glutathione and malondialdehyde content were not affected by ifosfamide at either dose. These findings indicate that ifosfamide produces abnormalities in rat renal function resembling subclinical Fanconi syndrome.

Analysis of Variance↗
PubMed2003

Chronic ifosfamide nephrotoxicity in children.

Nephrotoxicity is a frequent complication of treatment with ifosfamide in children. Although renal damage may be acute and reversible, chronic toxicity may develop with potentially serious consequences. Chronic nephrotoxicity due to ifosfamide may lead to a wide variety of subclinical and clinical manifestations. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis. Glomerular impairment is also common, whilst distal tubular impairment has been described but is relatively rare. Although full reversibility has been described occasionally, there is no information about the very long-term outcome of chronic ifosfamide nephrotoxicity. We studied a cohort of 12 children 1 and 10 years after completion of ifosfamide treatment. There was no statistically significant change in either glomerular or tubular toxicity in the group as a whole over this time period. However, marked improvements were seen in some aspects of toxicity in some patients, and deterioration was observed in others. We concluded that considerable nephrotoxicity is still present 10 years after completion of ifosfamide treatment, but that the outcome varies between individual patients. Although several risk factors for the development of chronic nephrotoxicity have been described, total ifosfamide dose, patient age at treatment, previous or concurrent cisplatin treatment, and unilateral nephrectomy are the most important. Nevertheless, it remains difficult to predict the occurrence of this toxicity with confidence. The pathogenesis of ifosfamide nephrotoxicity is poorly understood. There is an urgent need for the development and clinical investigation of nephroprotective strategies.

Antineoplastic Agents, Alkylating↗
PubMed1989

Toxicity of high-dose ifosfamide in children.

Ifosfamide has been shown to be an active agent in the treatment of several childhood cancers. However, the optimal dose and method of administration remains to be established. The dose/response relationship of ifosfamide suggests that a maximum tolerable, fractionated dose be given, and to reduce hospitalisation this dose should be given in the shortest possible time. A total of 20 patients aged 1-23 years received 124 courses (mean, 6 courses/patient; range, 1-16); 9 subjects had either relapsed or resistant disease, and all of these had previously received cyclophosphamide. A dose of 3 g/m2 ifosfamide was given for 2 (five patients) or 3 (15 patients) successive days. In all, 9 patients received the drug twice daily as a bolus and 11 were given a continuous infusion. All patients received 3 g/m2 mesna per day with ifosfamide and for 12 h there after, and hydration was maintained with 3 l/m2 fluid daily. Myelosuppression occurred in all patients but was mild and reversible, with no toxic deaths. On four occasions in three patients treatment had to be delayed due to myelosuppression. Seven episodes of fever and neutropaenia were successfully treated with antibiotics. The mean glomerular filtration rate in 13 patients at the start of treatment was 104 ml/min per 1.73 m2 and at the end was 92 ml/min per 1.73 m2. In all, 19 patients had microscopic and 1 macroscopic haematuria, with no clinical sequelae. Two patients with grossly impaired renal function following previous cisplatin therapy may have been precipitated into terminal renal failure by the ifosfamide therapy. Only one person developed neurotoxicity, which recurred on further treatment with ifosfamide but was fully reversible. All patients had moderate to severe vomiting, which was controlled with anti-emetics. No abnormalities of liver or cardiac function were detected. We conclude that ifosfamide given by this schedule is safe in patients with normal renal function.

Adolescent↗
PubMed1981

Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test.

The activated metabolites of ifosfamide and cyclophosphamide (4-hydroxy-ifosfamide and 4-hydroxy-cyclophosphamide) were analysed fluorometrically by condensation of liberated acrolein with m-aminophenol yielding 7-hydroxyguinoline. Interfering fluorescence of blood and urine was eliminated by extraction with dichlormethane and determination of blanks in which the liberated acrolein reacted with hydrazine to non-fluorescent pyrazoline. The modified test proved effective in identifying low levels of activated metabolites in man. After i.v. injection of 20 mg/kg cyclophosphamide or ifosfamide peak levels of activated cyclophosphamide (4.7 nmol/ml) and the area under the curve (c.t = 16.7 nmol.ml/h) showed mean values three times higher than those found for activated ifosfamide. One per cent of the applied dosis of cyclophosphamide vs. 0.3% of ifosfamide was excreted as activated metabolites. Due to the high stability of activated cyclophosphamide and ifosfamide in urine a low liberation rate of acrolein was found, the concentration of which in urine was below 0.5 nmol/ml. Acrolein, which was directly liberated from activated cyclophosphamide or ifosfamide, does not seem to play an important role in the urotoxicity of these cytostatics.

Acrolein↗
PubMed1990

Ifosfamide with and without adriamycin in advanced uterine leiomyosarcoma.

Uterine leiomyosarcomas are rare tumours and the results of treatment of advanced disease are poor. Ifosfamide and Adriamycin are both known to be active drugs in soft-tissue sarcomas. We present our experience using ifosfamide alone and in combination with Adriamycin in advanced or recurrent uterine leiomyosarcomas. Ifosfamide alone was given as a 24-h infusion at doses ranging from 5 to 7.5 g/m2, with mesna rescue. In the combination regimen, ifosfamide was given at a dose of 5 g/m2 and Adriamycin, at a dose of 40 or 60 mg/m2. Ten patients were treated with ifosfamide alone, with only one partial response lasting 6 months. In all, 11 patients were treated with ifosfamide and Adriamycin, which resulted in 1 complete response that lasted 11 months. Although many of the patients had extensive disease and some had undergone prior treatment with other chemotherapy, ifosfamide would appear to have only modest activity at the dose and schedule used.

Adult↗
PubMed1991

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗
PubMed1990

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗