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PubMed1994

Synovial sarcoma. Uniform response of metastases to high dose ifosfamide.

BACKGROUND: This report describes the unusually high response rate of metastatic synovial sarcoma to high dose ifosfamide (14-18 g/m2) when that drug was used to treat 13 consecutive patients with recurrent metastatic synovial sarcoma before surgery (or thoracotomies) to provide optimal salvage therapy for these patients. PATIENTS AND METHODS: Thirteen patients with recurrent or pulmonary metastatic synovial sarcoma seen at the Cedars-Sinai Comprehensive Cancer Center (Los Angeles, CA) from April, 1989 through January, 1993 were treated with high dose ifosfamide (14-18 g/m2). Ifosfamide was infused at the dose of 2 g/m2 over a 4-hour bolus infusion, followed by 2-g/m2 24-hour continuous infusions of ifosfamide, for a total of 14 or 18 g/m2 (6-8 days). Mesna (Mesnex, Bristol-Myers Oncology, Princeton, NJ) was infused with the ifosfamide at equimolar doses. Supplemental sodium bicarbonate (180 mEq) was given daily to prevent severe acidosis. Nine of the thirteen patients were treated with prior chemotherapy for their primary tumors. Prior chemotherapy consisted of doxorubicin (Adriamycin, Adria Labs, Dublin, OH) in all patients and doxorubicin combined with cisplatin in eight of them. RESULTS: All 13 patients had objective responses to high dose ifosfamide chemotherapy. There were nine partial responses and four complete responses. Five of the patients died of disease at 20-40 months (median, 27 months) from initial therapy. Eight patients have survived from 2 to 43 months (median, 20 months) from initial therapy, and three of these patients are disease free. Those patients surviving disease free had successful surgical removal of their residual metastatic disease after chemotherapy. CONCLUSION: Metastatic synovial sarcoma appears to be particularly sensitive to high dose ifosfamide chemotherapy. This experience suggests that there is a role for high dose ifosfamide chemotherapy in preoperative and postoperative adjuvant chemotherapy for primary synovial sarcoma, which is usually always a high grade malignant lesion with a poor prognosis after surgery alone.

Adolescent↗
PubMed1995

Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients.

BACKGROUND: Chronic renal failure has been described only rarely in patients treated with the alkylating agent ifosfamide, which is known to cause renal tubular dysfunction and acute renal failure, and the associated histopathologic features have not been well characterized. METHODS: This report describes the clinical course and renal histopathologic features in two patients in whom irreversible renal failure occurred requiring permanent dialysis after treatment with ifosfamide. RESULTS: Irreversible renal failure developed in a 60-year-old man with malignant fibrohistiocytoma, requiring chronic dialysis within several months after he received two cycles of ifosfamide in a cumulative dose of 28 g/m2. The second patient, a 53-year-old man with osteogenic sarcoma, received two cycles of ifosfamide with a cumulative dose of 26 g/m2, after initial therapy with cisplatin and doxorubicin. His renal function worsened over the next 11 months, at which time permanent dialysis was initiated. In neither patient were other causes of renal failure apparent. Renal biopsies in both patients showed diffuse tubular epithelial damage with degenerative and regenerative epithelial changes, diffuse interstitial fibrosis, and arterial and arteriolar sclerosis. CONCLUSIONS: Irreversible severe renal failure, which appears due to nephrotoxic damage of renal tubular epithelium and/or the renal microvasculature may develop after treatment with ifosfamide. Neither large cumulative doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment.

Antineoplastic Agents, Alkylating↗
PubMed1995

A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults.

BACKGROUND: Ifosfamide has been associated with proximal renal tubular dysfunction resembling Fanconi-like syndrome and leading to rickets in young children. The characteristic manifestations of this nephrotoxicity include phosphaturia and hypophosphatemia, glycosuria, aminoaciduria, renal tubular acidosis, and urinary loss of low molecular weight serum proteins. However, the relationship between acute ifosfamide nephrotoxicity, which is frequently subclinical, and long term renal damage is unclear. In this prospective study, the laboratory features of ifosfamide-induced acute nephrotoxicity were characterized further and correlated with the development of chronic nephropathy. METHODS: The renal function of newly diagnosed children and young adults with high risk sarcomas was followed during therapy with a high dose ifosfamide-containing regimen. Serum and urine were collected regularly immediately before and after 5-day cycles of ifosfamide throughout treatment for determination of the fractional excretion of electrolytes (sodium, potassium, phosphate, magnesium, calcium) and glucose and urinary excretion of amino acids and beta 2-microglobulin. RESULTS: Significant changes in the renal threshold of phosphate excretion, the fractional excretion of calcium and glucose, and the urinary excretion of beta 2-microglobulin were observed when comparing pretreatment values with those at the end of a 5-day treatment cycle. The median renal threshold of phosphate excretion decreased from 1.22 to 0.82 mmol/L (P < 0.0001). The median fractional excretions of calcium and glucose increased from 1.05% to 1.68% (P < 0.0001) and 0.05% to 0.08% (P = 0.0006), respectively. Beta 2-microglobulin excretion increased by 70-fold from 0.02 to 1.42 mg/mmol (P < 0.0001). Except for glucose and beta 2-microglobulin excretion, renal parameters returned to baseline before the next ifosfamide treatment cycle. Acute aminoaciduria was observed in 21 of 23 patients. Chronic nephrotoxicity, as defined by the development of a Fanconi-like syndrome or chronic tubular electrolyte loss requiring oral supplementation, developed in the three patients with the highest urinary excretion of beta 2-microglobulin after ifosfamide therapy. CONCLUSIONS: Prospectively, high dose ifosfamide was associated with a 4% incidence of Fanconi-like syndrome; however, evidence of acute reversible subclinical nephrotoxicity was observed for all patients. Severe beta 2-microglobulinuria appeared to be a prognostic laboratory indicator for the development of chronic nephrotoxicity.

Adolescent↗
PubMed1975

Pharmacokinetics of ifosfamide.

A multicompartment pharmacokinetic model for ifosfamide has been employed using a system of first-order differential equations, which includes a term for metabolism according to Michaelis-Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisfactorily accounts for all the administered drug. The pseudometabolic rate constant for ifosfamide in man is found to be less than 20 percent of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosfamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.

Antineoplastic Agents↗
PubMed2000

A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study.

OBJECTIVE: The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide-cisplatin in this patient population. METHODS: Patients were randomized to receive ifosfamide (1.5 g/m(2)/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m(2)/day) times 5 days. No patient had received previous chemotherapy. RESULTS: Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin-ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide-cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for "other" metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test). CONCLUSION: The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.

Adult↗
PubMed2006

Ifosfamide toxicity in cultured proximal renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that ifosfamide metabolites, particularly chloroacetaldehyde, produced within the kidney contribute to nephrotoxicity. The present study examined the effects of ifosfamide and its metabolites, chloroacetaldehyde and acrolein, on rabbit proximal renal tubule cells in primary culture, using a transwell culture system that allows separate access to apical and basolateral cell surfaces. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde-and acrolein-induced renal cell injury was also assessed. Ifosfamide (2,000-4,000 microM) did not affect transcellular inulin diffusion but caused a modest but significant impairment in organic ion transport; this impairment was greater when ifosfamide was added to the basolateral compartment of the transwell. Chloroacetaldehyde and acrolein (6.25-100 microM) produced dose-dependent impairments in transcellular inulin diffusion and organic ion transport. Chloroacetaldehyde was a more potent toxin than acrolein. Co-administration of mesna or amifostine prevented metabolite toxicity. Amifostine was only protective when added to the apical compartment of transwells. These results show that ifosfamide is taken up by renal tubule cells preferentially through their basolateral surfaces, and supports the hypothesis that chloroacetaldehyde is primarily responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity in vivo.

Acetaldehyde↗
PubMed2005

[Ifosfamide induced encephalopathy: 15 observations].

INTRODUCTION: Ifosfamide is an alkylating agent used in the treatment of germ-cell tumors, sarcomas and lymphomas. One of its main side effects is the encephalopathy of which the incidence may reach 30% in the literature, in adults and children just as well. OBJECTIVES: Based on both our experience and a review of the literature, we propose some recommendations for the management of this complication. PATIENTS AND METHODS: We report 15 encephalopathy cases in non-brain tumor patients, which occurred between January 1987 and March 2002 in children from 2 to 17 years old, treated for solid tumors at the Institut Gustave Roussy. Ifosfamide was administered at a posology between 5.4 and 15 g/m(2)/course, associated with other antimitotics such as actinomycin D, etoposide or vincristine. RESULTS: Six patients experienced a grade III neurological toxicity according to the NCI classification, which developed as excess drowsiness lasting up to 36 hours. Six other patients developed grade IV neurotoxicity, including two comas resolving within 4 days and four short generalized convulsions. Three other children experienced grade II drowsiness. Brain MRIs were normal and EEG showed an aspecific encephalopathy tracing. This early central neurotoxicity appeared right from the first administration, and occurred immediately after the first injection or during the second or third day of treatment. It was most often reversible, usually 3 to 5 days after the last ifosfamide administration. Five patients were administered a treatment with Methylene Blue with a demonstrable efficacy in only one case. No death or neurological sequelae have been noted. Ifosfamide has been renewed after the neurological accident in 7 of those patients. Only 1 of those 7 patients developed grade IV neurotoxicity during the next course of treatment. In 2 of those 7 children, Methylene Blue was used in a prophylactic way. No neurological disorders have been noted during the next courses of treatment. DISCUSSION: In the literature, the following are described as risk factors for ifosfamide encephalopathy: advanced pelvic disease, previous cisplatyl treatment and renal failure. We have not found any of these predisposing factors in our series, but three of the fifteen patients had severe neurotoxicity associated with Vincristin during previous treatments. CONCLUSION: Facing a clinical diagnosis of ifosfamide encephalopathy, it is recommended to discontinue administration of ifosfamide and inject by intravenous route 50 mg Methylene Blue every 4 hours until the symptomatology recedes. The re-challenge of Ifosfamide is not contra-indicated and should be performed under prophylactic treatment with Methylene Blue by intravenous route at the dose of 50 mg every 6 hours.

Adolescent↗
PubMed2004

Mesna ameliorates intestinal mucosa damage after ifosfamide administration in the rabbit at a dose-related manner.

BACKGROUND: Cancer chemotherapy may lead to mucositis, a serious dose-limiting side effect. The alkylating agent ifosfamide is used in the treatment of various forms of cancer in combination with the uroprotective thiol mesna (2-mercaptoethane-sulfonate). The aims of this study were to assess the dose response intestinal mucosa damage of ifosfamide and to investigate the potential protective effect of mesna on rabbit intestinal epithelium. MATERIALS AND METHODS: Fifty New Zealand White rabbits were randomly assigned to 10 groups of five animals each and received intravenously every week for 10 weeks either normal saline, ifosfamide, mesna, or ifosfamide plus mesna at three escalating dose levels (ifosfamide: 30, 45, or 60 mg/kg; mesna: 12, 18, or 24 mg/kg divided into two equal doses administered 4 h apart). Intestinal mucosa damage was assessed on the basis of crypt cell apoptosis and proliferation as well as intestinal morphometry. Apoptosis was detected by agarose gel electrophoresis and quantified by the DNA fragmentation assay and a standard terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method by which the percentage of fragmented DNA and the apoptotic index were determined, respectively. The mitotic index and the crypt-villus (c/v) unit height were also measured in histological sections. RESULTS: Ifosfamide caused a dose-related increase of crypt cell apoptosis and shortening of c/v unit, while it had a steady antimitotic effect. Mesna as a sole agent had no apoptotic or trophic effect on intestinal mucosa and hence no effect on intestinal morphometry. However, mesna, when administered concurrently with ifosfamide, ameliorated apoptosis, hypoproliferation, and mucosal atrophy at a dose-related manner. CONCLUSIONS: Ifosfamide causes intestinal mucosa damage, which may be ameliorated in a dose-related manner by coadministration of mesna.

Animals↗
PubMed2002

Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588).

This randomized study of previously untreated patients with extensive disease small cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anti-cancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. One hundred and thirty-five patients were randomly assigned to receive as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m(2)), doxorubicin (50 mg/m(2)) and vincristine (1.4 mg/m(2)) every 3 weeks--or the phase II drugs ifosfamide (1.5 gm/m(2)/days 1-5) with mesna (300 mg/m(2)) dose at 0, 4 and 8 h after IV daily ifosfamide every 3 weeks or teniposide (60 mg/m(2)/days 1-5) every 3 weeks. Nonresponders received salvage chemotherapy-etoposide (120 mg/m(2) on days 1, 2 and 3) and cisplatin (60 mg/m(2) on day 1), repeated every 3 weeks. Among the 46 patients on CAV, there were two complete and 24 partial responses (56%). Among the 43 patients on ifosfamide, there were three complete and 18 partial responses (49%), while among the 46 patients on teniposide, there were two complete and 18 partial responses (43%). Eighty-three of the patients proceeded onto salvage regimen, of which 81 were analyzable for response and toxicity. Among the 81 patients who continued on salvage therapy and were evaluable for response, the overall best response rate was 61% for CAV+salvage, 54% for ifosfamide+salvage, and 53% for teniposide+salvage. These rates were not significantly different (P=0.962). Of the 135 analyzable patients, 130 (96%) have died. The estimated median survival time was 42 weeks for CAV patients, 43 weeks for ifosfamide, and 38 weeks for teniposide. Seven patients survived longer than 2 years (four on CAV, one on ifosfamide and two on teniposide). There were 29 life-threatening complications to the induction regimen (22 (48%) on CAV, four (9%) on ifosfamide and three (7%) on teniposide) and seven lethal complications (two on CAV, four on ifosfamide and one on teniposide). The treatments were significantly different with respect to the overall degree of toxicity (P < 0.0001) with CAV being more toxic. The data of this study, like the previous ECOG study suggests that the administration of a new agent followed by effective salvage chemotherapy in the treatment of extensive disease small cell lung cancer may have no adverse effect on survival.

Adult↗
PubMed1999

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Adult↗
PubMed1998

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK).

UNLABELLED: Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.

Adolescent↗
PubMed1994

Efficacy of ifosfamide, dacarbazine, doxorubicin and cisplatin in human sarcoma xenografts.

The primary chemosensitivity of 16 highly malignant xenografted human soft-tissue sarcomas to ifosfamide, dacarbazine, adriamycin and cisplatin and the development of secondary drug resistance in two chemosensitive sarcoma cell lines was tested in the xenograft system. Single-dose, single-agent treatments with 350 mg kg-1 ifosfamide, 200 mg kg-1 dacarbazine, 10 mg kg-1 doxorubicin and 6.6 mg kg-1 cisplatin were administered and response measured as specific growth delay. Since ifosfamide induced unexpectedly higher toxicity, response was corrected based on the shape of the dose-response curve for ifosfamide. Taking a specific growth delay > 3 as the cut-off point for chemosensitivity, ifosfamide, dacarbazine, doxorubicin and cisplatin were effective in 10/16, 4/16, 2/16 and 1/16 sarcoma cell lines respectively. Five out of 16 sarcoma cell lines were resistant to all tested drugs. Ifosfamide-resistant sarcoma lines were also resistant to doxorubicin and cisplatin, indicating a high degree of cross-resistance. Dacarbazine was still effective in 1/6 ifosfamide-resistant sarcoma cell lines. Secondary drug resistance developed slowly after doxorubicin and ifosfamide pretreatments at moderate selection pressure and developed rapidly after dacarbazine pretreatment at high selection pressure.

Animals↗
PubMed1998

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours.

Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated 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-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.

Adult↗
PubMed2004

CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes.

Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n=11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg(protein)(-1). CYP2C9 (n=9) was present in all tested breast tumour samples, too, while CYP2B6 (n=10) protein could not be detected. All measured breast cancer microsomes (n=4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min(-1) mg(protein)(-1), while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.

Aged↗
PubMed2000

Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM.

AIMS: This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m-2 ifosfamide by means of a 72 h continuous i.v. infusion. METHODS: A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction. RESULTS: The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 +/- 0.27 l h-1, 43.5 +/- 2.9 l, 0.0546 +/- 0. 0078 h-1, 12.7 h and 30.7 +/- 4.8 microM, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 microM, respectively. CONCLUSIONS: The absence of a lag time for the autoinduction of ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.

Adult↗
PubMed2000

Pharmacokinetics of ifosfamide are changed by combination with docetaxel: results of a phase I pharmacologic study.

The pharmacokinetics of the combination of docetaxel and ifosfamide were studied in a phase I study. Docetaxel was given to cancer patients as a 1-hour infusion followed by a 24-hour infusion of ifosfamide (schedule A). After the dose-limiting toxicity of the combination was reached, ifosfamide was administered as a 24-hour infusion followed after 24 hours by a 1-hour infusion of docetaxel (schedule B). Cycle duration was 21 days. Docetaxel was determined by high-performance liquid chromatography, and ifosfamide and its metabolites, by gas chromatography-mass spectrometry. Twenty-seven patients were treated according to schedule A, and 6 according to schedule B. Combining the two drugs did not change their respective plasma half-lives. The sequence of drug administration did not affect the clearance and the area under the curve (AUC) of docetaxel. There was a decrease in the AUC of ifosfamide in schedule A compared with schedule B, resulting from an increase in the clearance of ifosfamide. The pharmacokinetics of docetaxel are not influenced by combination with ifosfamide, regardless of the drug sequence, but ifosfamide pharmacokinetics are changed by docetaxel, depending on the sequence of administration. The increase of clearance in schedule A may be due to the pretreatment with corticosteroids.

Adult↗
PubMed1997

Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation.

Cyclophosphamide and ifosfamide are alkylating agent prodrugs that require activation by cytochrome P450 (CYP) to manifest their cancer chemotherapeutic activity. The present study investigates the activity of four individual human CYP2C enzymes and their allelic variants in cyclophosphamide and ifosfamide activation as an initial attempt to gain insight into the underlying basis for the large interpatient differences in the clinical pharmacokinetics and metabolism of these anticancer drugs. Recombinant CYP2C8, CYP2C19, two allelic variants of CYP2C18, and six variants of CYP2C9 expressed in a yeast cDNA expression system were each enzymatically active, as judged by the ability of the isolated microsomes to catalyse 7-ethoxycoumarin O-deethylation after reconstitution with purified NADPH-cytochrome P450 reductase and cytochrome b5. With cyclophosphamide as substrate, CYP2C19 had the lowest apparent Km, followed by CYP2C9, CYP2C18 and CYP2C8, whereas in the case of ifosfamide, the rank order was: Km CYP2C19 < CYP2C18 < CYP2C9 < CYP2C8. CYP2C18 had the highest in vitro intrinsic clearance/catalytic efficiency (apparent Vmax/Km) in cyclophosphamide and ifosfamide activation, followed by 2C19 > 2C9 approximately 2C8. Examination of a panel of CYP2C allelic variants revealed that CYP2C18-Thr385 had both a higher Vmax and a higher apparent Km toward cyclophosphamide than CYP2C18-Met385 with no difference in catalytic efficiency, whereas with ifosfamide the Thr385 allele exhibited a strikingly lower apparent Km resulting in a six-fold higher catalytic efficiency. In the case of CYP2C9, a Ile359 to Leu mutation associated with poor metabolism of the hypoglycemic drug tolbutamide decreased catalytic efficiency toward cyclophosphamide by increasing the apparent Km, whereas the same mutation reduced the efficiency of this P450 toward ifosfamide by decreasing the Vmax. Substitution of CYP2C9-Gly417 by Asp resulted in a two-fold lower catalytic efficiency for cyclophosphamide metabolism but a three-fold higher efficiency for ifosfamide metabolism. A His276 to Gly substitution resulted in an increase in both Vmax and apparent Km with no net change in catalytic efficiency for either oxazaphosphorine. Mutations at CYP2C9 residues 144 and 358 had little or no effect. Thus (a) wild type CYP2C19 and CYP2C9 are relatively low Km catalysts of cyclophosphamide and ifosfamide activation, and (b) all four human CYP2C enzymes activate these two anticancer prodrugs with varying efficiencies and with striking differences among naturally occurring allelic variants in the case of CYP2C9 and CYP2C18.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2005

Role of GSTM1, GSTP1, and GSTT1 gene polymorphism in ifosfamide metabolism affecting neurotoxicity and nephrotoxicity in children.

The aim of this study was to evaluate the impact of GSTM1, GSTT1, and GSTP1 gene polymorphism on urinary excretion of unchanged ifosfamide, 2-dechloroethylifosfamide (2DCIF), and 3-dechloroethylifosfamide (3DCIF) with regard to the incidence of ifosfamide-related nephrotoxicity and neurotoxicity in children. The study comprised 76 children (38 girls, 38 boys) ages 9.84 to 210 months who were being treated for various malignant diseases with ifosfamide. The children were enrolled after identification of genotype coding for three classes of glutathione S-transferases (GSTM1, GSTT1, and GSTP1) at the initial stage of diagnosis. (P) nuclear magnetic resonance spectroscopy was used to analyze the urinary excretion of unchanged ifosfamide, 2DCIF, and 3DCIF metabolites on consecutive days after the end of the 3-hour infusion of ifosfamide. In children with polymorphic locus of the GSTP1 gene compared with children with homozygous wild alleles, increased urinary excretion of 3DCIF (P=0.029) and decreased creatinine clearance was found (Mann-Whitney P=0.03; median 81.1 mL/min/1.73 m vs. 105.0 mL/min/1.73 m, respectively). The authors' multidimensional analysis model revealed that besides the total ifosfamide dose and co-administration of other toxic drugs, polymorphic locus of GSTP1 gene may be one of the factors determining a higher toxicity of the cytostatic agent. The model was construed at P=0.029. Moreover, no correlation was found between the GSTM1 or GSTT1 genotype and ifosfamide toxicity and the urinary excretion of its metabolites. The results of this analysis indicate that individual reactions to ifosfamide can depend on inherited genetic polymorphisms, especially associated with the GSTP1 gene coding detoxifying enzyme.

Adolescent↗