Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Ifosfamide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1998

Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms' tumor.

PURPOSE: We evaluated the in vitro hemodialysis ratio and subsequent toxicity and pharmacokinetics of ifosfamide in an anephric patient with Wilms' tumor. METHODS: An in vitro model was used to determine the extraction ratio of ifosfamide by dialysis. The toxicity and plasma concentrations of ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were then determined over 24 h after a single 1.6 g/m2 dose of ifosfamide. Plasma concentrations were also measured before and after ten dialysis sessions during four courses of ifosfamide therapy. RESULTS: The in vitro hemodialysis model showed that ifosfamide was cleared with an extraction ratio of 86.7+/-0.5% and remained constant even at low concentrations of drug. The mean decrease in vivo following hemodialysis for ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were 86.9%, 77.2%, and 36.2%, respectively. The pharmacokinetic parameters for ifosfamide using model-independent methods were calculated: Vd = 0.23 l/kg, t1/2 = 4.8 h, and ClT = 3.30 l/h per m2. Ifosfamide-associated neurotoxicity was noted within hours of drug administration and improved rapidly following hemodialysis. CONCLUSIONS: The results of our study suggest that the pharmacokinetics of parent ifosfamide may not be substantially altered in patients with renal failure. Hemodialysis was shown to remove ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide from the blood stream. Hemodialysis was also shown to reverse ifosfamide-related neurotoxicity.

Antineoplastic Agents, Alkylating↗
PubMed2002

Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide.

PURPOSE: The aim of the present study was to determine the turnover (4-hydroxylation and N-dechloroethylation) of ifosfamide in a total of 25 human liver microsomal preparations in which the codetermination of keto- and carboxyifosfamide as well as the calculation of free and protein-bound acrolein was carried out for the first time. METHODS: The 4-hydroxylation of ifosfamide was estimated by using acrolein (free and protein-bound) and a newly developed procedure involving the codetermination of keto- and carboxyifosfamide (LC/MS). The ifosfamide N-dechloroethylation was determined as the sum of 2- and 3-dechloroethylifosfamide (LC/MS). RESULTS: Using the usual estimation of liberated free acrolein in 25 human liver microsomal preparations, the 4-hydroxylation of ifosfamide amounted to 0.28+/-0.16 nmol/min. nmol(P450). However, after calculating the 4-hydroxylation as the sum of free and protein-bound acrolein and keto- and carboxyifosfamide, a ninefold higher activity (2.40+/-0.73 nmol/min. nmol(P450)) was found. The percentage of the inactive metabolites keto- (25/25) and carboxyifosfamide (5/25) in the 4-hydroxylation amounted to only 0.79-5.25% (mean 2.90%). The ifosfamide N-dechloroethylation (mean 0.21+/-0.11 nmol/min. nmol(P450)) determined as the sum of 2- and 3-dechloroethylifosfamide was estimated as 8.3+/-4.3% of the total ifosfamide turnover. The application of the relative substrate-activity factor (RSF)-approach and the calculation of the contribution of various isoforms in the ifosfamide 4-hydroxylation yielded the following results: CYP 3A4: 58+/-31%, CYP 2A6: 25+/-15%, and CYP 2C9: 5+/-2% of the total measured 4-hydroxylation. A correlation between 4-hydroxylation and the N-dechloroethylation rates of ifosfamide and the activities of isoenzymes indicates the involvement of both CYP 3A4 ( P=0.026) and CYP 2C9 ( P=0.012) in the 4-hydroxylation reaction and of CYP 3A4 ( P<0.01) in the N-dechloroethylation reaction. CONCLUSIONS: The estimation of protein-bound acrolein should be included in the calculation of the ifosfamide 4-hydroxylation besides liberated free acrolein. Because of the small amounts of the inactive metabolites keto- and carboxyifosfamide, the exclusive determination of acrolein only (free and protein-bound) seems to suffice for the calculation of total ifosfamide hydroxylation. Using this method the hepatic in vitro turnover of ifosfamide was estimated as 92% for 4-hydroxylation (CYP 3A4 and CYP 2A6 mediated) and 8% for N-dechloroethylation (CYP 3A4 mediated), and in this way, a relative overestimation of the N-dechloroethylation of ifosfamide on the whole metabolism is avoided.

Acrolein↗
PubMed2001

Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites.

The anticancer drug ifosfamide is a prodrug requiring activation through 4-hydroxyifosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of ifosfamide leads to 2- and 3-dechloroethylifosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for ifosfamide and increased for 3-dechloroethylifosfamide compared with short infusion durations. No differences in dose-normalized exposure to ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylifosfamide. The observed dose and infusion duration dependence should be taken into account when modeling ifosfamide metabolism.

Antineoplastic Agents, Alkylating↗
PubMed1993

A phase I trial of ifosfamide, mesna, and cisplatin in advanced non-small cell lung cancer. A cancer and leukemia group B study.

BACKGROUND: This Phase I study was designed to determine the maximum tolerated dose of ifosfamide-mesna with a fixed dose of cisplatin without growth factor or hematopoietic precursor support. METHODS: Twenty-five patients with previously untreated advanced non-small cell lung cancer were treated at four dose levels. Initially, the cisplatin dose was 100 mg/m2 given on day 1. Seven patients were treated with ifosfamide 2.0 g/m2 days 1 to 3, and six patients received ifosfamide 2.5 g/m2 days 1 to 3. Mesna was given at 20% of the ifosfamide dose at 0, 4, and 6 hours after ifosfamide. Cycles were repeated every 4 weeks. RESULTS: Dose-limiting toxicities (myelosuppression and renal toxicity) were seen at dose level 2 (ifosfamide 2.5 g/m2). Because 5 of the first 13 patients experienced Grade 3 renal toxicity, the study was amended to give cisplatin in divided doses. An additional six patients each were treated at dose level 3 (ifosfamide 2.0 g/m2 days 1-3) and dose level 4 (ifosfamide 2.5 g/m2 days 1-3) with cisplatin 33 mg/m2 days 1 to 3. Dose-limiting toxicity (myelosuppression) was reached at ifosfamide 2.5 g/m2. No further Grade 3 renal toxicity was seen. Grade 3 or worse toxicities were seen as follows: neutropenia 80%, thrombocytopenia 48%, nausea/vomiting 36%, anemia 32%, renal 20%, central nervous system 16%, and infection 16%. Two toxic deaths occurred, both with infection, renal failure, and neutropenia. Partial responses were seen in 8 of 25 eligible patients (32%). CONCLUSIONS: The maximum tolerated dose in this group of patients was defined as ifosfamide 2.0 g/m2 days 1 to 3 when given with cisplatin 33 mg/m2 days 1 to 3. When combining high-dose cisplatin with ifosfamide, it is advisable to give cisplatin in divided doses.

Adult↗
PubMed2006

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Adult↗
PubMed2001

Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients.

The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.

Adult↗
PubMedDate not supplied

Glutathione conjugation of the cytostatic drug ifosfamide and the role of human glutathione S-transferases.

Development of drug resistance against alkylating cytostatic drugs has been associated with higher intracellular concentrations of glutathione (GSH) and increased expression of glutathione S-transferase (GST) enzymes. Therefore, enhanced detoxification by the glutathione/glutathione S-transferase pathway has been proposed as a major factor in the development of drug resistance toward alkylating agents. In this paper we describe 31P NMR and HPLC studies on the spontaneous and glutathione S-transferase catalyzed formation of glutathionyl conjugates of two metabolites of ifosfamide, i.e., 4-hydroxyifosfamide and ifosfamide mustard. At 25 degrees C activated ifosfamide (= 4-hydroxyifosfamide + aldoifosfamide) disappeared faster in the presence of a 10-fold excess of GSH (t1/2 = 107 min) compared to incubations without GSH (t1/2 = 266 min). No evidence for the formation of 4-glutathionyl ifosfamide was found. The ultimate alkylating species of ifosfamide is ifosfamide mustard (IM). In the absence of glutathione, the rate constant for the disappearance of the ifosfamide mustard signal at 25 degrees C (pH 7) was 1.98 x 10(-3) min-1 (t1/2 = 350 min). In the presence of a 10-fold molar excess of glutathione, this rate constant was 1.95 x 10(-3) min-1 (t1/2 = 355 min), indicating that the spontaneous formation of an aziridinium ion is the rate-limiting event in the reaction with glutathione. The aziridinium ion formed from IM can deprotonate upon formation, leading to the formation of a (noncharged) aziridine species. This intermediate (N-(2-chloroethyl)-N'-phosphoric acid diamide) was characterized by 31P, 1H, and 13C NMR spectra. When 2 mM ifosfamide mustard was incubated with 1 mM GSH in the presence of 40 microM GST P1-1, the formation of monoglutathionyl ifosfamide mustard was 2.3-fold increased above the spontaneous level. The other major human isoenzymes tested (A1-1, A2-2, and M1a-1a) did not influence the formation of monoglutathionyl ifosfamide mustard. The results of these studies demonstrate that increased levels of GST P1-1 can contribute to an enhanced detoxification of ifosfamide.

Antineoplastic Agents, Alkylating↗
PubMed1986

Pharmacokinetics and bioavailability of oral ifosfamide.

The bioavailability of oral N,3-bis(2-chloroethyl) tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (ifosfamide) (500-mg gelatine capsules) was investigated in 18 patients with bronchogenic carcinoma. Oral and intravenous (Holoxan) ifosfamide was applicated in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n = 12) and 2 g/m2 (n = 6). Ifosfamide determination was performed with N/P flame ionization gas chromatography following derivatization with heptafluorobutyric acid. Orally administered ifosfamide showed relatively fast absorption kinetics. Peak levels were reached within 1 h in both dosage groups. With exception of the absorption phase blood level curves of orally and i.v. administered ifosfamide were identical. The average half-life of ifosfamide was 5.5 h (2 g/m2) and 5.8 h (1 g/m2) with a considerable individual variation in both dosage groups. The bioavailability of oral ifosfamide calculated as ration AUCp.o./AUCi.v. was 1.04 after 1 g/m2 ifosfamide and 0.95 in the 6 patients receiving 2 g/m2 ifosfamide. According to our results i.v. administration of ifosfamide especially in fractioned dosage regimes can be replaced by oral application of the same ifosfamide dose.

Administration, Oral↗
PubMedDate not supplied

Ifosfamide metabolism and pharmacokinetics (review).

In this article the studies on the pharmacokinetics and metabolism of ifosfamide have been summarised. Ifosfamide is a pro-drug and requires metabolic activation to exert cytotoxic activity. The various metabolites determined after oral or intravenous administration of ifosfamide show a large inter- and intrapatient variability. Oral and intravenous fractionated treatment with ifosfamide exhibits a time-dependent increase in ifosfamide metabolic clearance which is explained by a mechanism of auto-induction of the hepatic oxygenase system. The pharmacokinetic parameters of ifosfamide do not correlate with age, sex and weight. Oral ifosfamide, at a dose higher than 1 g/m2, induces neurotoxicity in a high percentage of patients. In these cases the pharmacokinetics of ifosfamide were not aberrant. This implies that ifosfamide metabolites rather than the parent drug are likely to be responsible for the neurotoxicity. The development of more selective and sensitive analytical methodologies are necessary in order to go in more insight into the disposition of the active ifosfamide metabolites, including their clinical effects. This may lead to a further optimisation of the therapeutic use of ifosfamide.

Aging↗
PubMed1993

Ifosfamide with mesna uroprotection and etoposide in recurrent, refractory acute leukemia in childhood. A Pediatric Oncology Group Study.

BACKGROUND: Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia. METHODS: Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage. RESULTS: Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive. CONCLUSIONS: The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.

Acute Disease↗
PubMed2005

Combined therapy of experimental pancreatic cancer with CYP2B1 producing cells: low-dose ifosfamide and local tumor irradiation.

Local therapy of pancreatic cancer with microencapsulated CYP2B1-producing cells and ifosfamide showed an effect both on the primary tumor and on distant metastatases. This possibly represents a consequence of the activation of immune response. Other studies have demonstrated that local tumor irradiation leads to the activation of the intratumoral lymphocyte infiltration. The aim of our study was to investigate the efficacy of the combined therapy with low-dose irradiation, ifosfamide and CYP2B1-producing cells. Syngenic pancreatic cancer was induced in 38 Lewis-rats by subcutaneous inoculation of 1 x 10(6) (DSL6A) tumor cells. Microencapsulated CYP2B1-producing cells were injected peritumorally 10--12 weeks after tumor implantation. Animals were randomized to the following groups: 1) control (NaCl, 1 ml i.p.), 2) ifosfamide (50 mg/kg, i.p., (3x/week), 3) local irradiation with 5 Gy and 4) ifosfamide plus irradiation. The tumor growth was monitored for 3 weeks. The tumor infiltration with CD4+, CD8+, NK-cells, microvessel density and proliferation rates were investigated by immunohistochemistry. Cytokine plasma level for TNF-alpha were measured by ELISA. Seven of 9 animals in the group of combined therapy showed an objective response to the therapy. The therapy with ifosfamide or radiation alone showed 5 and 3 responders, respectively. The mean tumor volume was significantly reduced after combined ifosfamide plus radiation therapy in the first week, whereas monotherapy with ifosfamide or radiation significantly decreased tumor growth earliest after 2 and 3 weeks, respectively. The high plasma level of TNF-alpha in the control group was significantly reduced after combined ifosfamide/irradiation treatment. The lymphocyte infiltration and tumor proliferation were not significantly different between the groups. Microvascular density was significantly increased after ifosfamide and ifosfamide plus irradiation therapy. The combination of ifosfamide/CYP2B1-producing cells and irradiation showed an earlier therapeutical effect on the growth of rat pancreatic cancer than the irradiation or ifosfamide alone. There was no evidence of late activation of lymphocyte infiltration and PCNA-positive tumor cells.

Animals↗
PubMed1991

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

1. We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens. Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2. After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t1/2,z of 5.4 h (3.6-10.4 h). The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-1. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-1. 3. When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t1/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

A phase I-II trial of high-dose ifosfamide in patients with ovarian cancer refractory or resistant to platinum and/or paclitaxel-containing chemotherapy.

AIMS AND BACKGROUND: To evaluate the toxicity of high-dose ifosfamide in ovarian cancer patients refractory or resistant to platinum and/or paclitaxel-containing chemotherapy. METHODS: This was an open, non-randomized phase I-II trial of high-dose ifosfamide. Eligibility criteria were: patients aged 18-75 years affected by ovarian cancer with refractory or resistant disease or early relapse after first-line treatment including platinum or paclitaxel. Three patients were given escalating ifosfamide doses; if no severe adverse events occurred, the ifosfamide dose was increased. The starting dose of ifosfamide was 10 g/m2 i.v. and the dose increase was 1 g/m2 every four weeks for a total of five courses; 12 g/m2 was the maximum ifosfamide dose to be administered. The trial then progressed to a phase II trial, in which ifosfamide was given at the maximum tolerated dose reached during the escalating dose phase. RESULTS: A total of 36 patients entered the trial. Nine patients were involved in phase I of the study; 3 received 10 g/m2 ifosfamide, 3 11 g/m2 and 3 12 g/m2. Of the 32 evaluable patients 6 (18.8%) achieved a complete response and three (9.4%) a partial response, giving an overall response rate of 28.1% (95% CI, 15-61% based on Poisson's approximation). The median number of ifosfamide courses was five. G1, G2 and G3 neurotoxicity was reported in 3 (8%), 2 (5%) and 2 (5%) patients, respectively. CONCLUSION: This phase I-II trial indicates that high-dose ifosfamide has some activity but also a relevant degree of toxicity in resistant or refractory platinum and paclitaxel-pretreated ovarian cancer.

Adult↗
PubMed2001

Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Animals↗
PubMed2000

Ifosfamide-based drug combinations: preclinical evaluation of drug interactions and translation into the clinic.

Ifosfamide is an alkylating antineoplastic agent with documented activity against a variety of solid tumor types, most notably lung cancer, testicular cancer, and sarcoma. Ifosfamide has been included in various drug combination protocols, usually on an empirical basis. To gather more insight into the mechanisms that underlie these drug interactions and to develop guidelines for further improvement of clinical combination protocols, we performed a broad preclinical evaluation program of ifosfamide-based combination regimens using isobologram analysis of drug interactions. In established cisplatin-sensitive and cisplatin-refractory ovarian carcinoma cell lines, a schedule-dependent drug interaction between paclitaxel and activated hydroperoxy-ifosfamide (4-OOH-IF) could be demonstrated. When both drugs were given for 2 hours, simultaneous exposure or the sequence of paclitaxel followed by 4-OOH-IF were additive or synergistic. In contrast, application of 4-OOH-IF before paclitaxel resulted in pronounced antagonism. Based on the sequence-dependent synergistic interactions a phase I trial was initiated with paclitaxel given on day 1 and ifosfamide given on days 2 to 5 in patients with cisplatin-refractory ovarian cancer. Four dose levels were evaluated in 18 patients. The maximum tolerated dose was paclitaxel 175 mg/m2 on day 1 and ifosfamide 2,000 mg/m2 on days 2 to 5, with central nervous system toxicity and nephrotoxicity being dose-limiting. The recommended dose for further evaluation of this combination was paclitaxel 175 mg/m2 on day 1 and ifosfamide 1,500 mg/m2 on days 2 to 5. Although all patients were heavily pretreated with multiple agents, nine of 18 patients achieved an objective response. Ifosfamide also has been shown to reduce cellular glutathione content; thus, a series of experiments evaluated the ability of activated cyclophosphamide or ifosfamide to deplete cellular glutathione in vitro. It was demonstrated that glutathione depletion is dose- and time-dependent, with 4-OOH-IF leading to a more pronounced suppression of cellular glutathione compared with 4-OOH-Cy. The decrease in cellular glutathione content was maximal at 2 hours after drug treatment; however, cellular glutathione levels returned to normal within 24 hours. When 4-OOH-IF was combined in vitro with cisplatin, schedule-dependent interactions again became obvious. The highest antitumor activity was seen when both drugs were given concurrently; sequential application with 4-OOH-IF given before cisplatin resulted in antagonism. Since adequate glutathione levels are necessary for multidrug resistance protein (MRP) function, glutathione depletion might lead to reversal of MRP-mediated drug resistance. Preliminary data showed that 4-OOH-IF significantly decreases glutathione concentrations in MRP-expressing human HT1080/DR4 sarcoma cells, leading to maximum steady-state reduction after a 90-min exposure to 4-OOH-IF. Taken together the data reported here demonstrate that in vitro ifosfamide may potentiate the antitumor activity of a variety of cytotoxic agents and therefore merits further clinical evaluation in drug combinations (eg, taxanes, anthracyclines).

Antineoplastic Agents, Alkylating↗
PubMed1990

Ifosfamide and mesna.

The chemistry, pharmacology, pharmacokinetics, and adverse effects of ifosfamide and mesna are described separately, followed by a discussion of the adverse effects of concurrent ifosfamide and mesna, the clinical spectrum of ifosfamide, and the dosage and administration of the two drugs. Ifosfamide, an active analogue of cyclophosphamide, differs from other direct alkylating substances in that it requires biotransformation in the liver before it can exert its alkylating effects. The bioavailability of ifosfamide after oral administration exceeds 95%. The adverse effects of ifosfamide include hematologic, urinary tract, GI tract, and CNS toxicity. Mesna is a thiol compound designed to function as a regional detoxificant of urotoxic oxazaphosphorine cytostatics such as ifosfamide. The drug is rapidly oxidized in the plasma to its dimeric form, dimesna, one third of which is converted back to mesna by glutathione reductase. The mean total urinary availability of mesna administered orally is 76%. Mesna may produce gastrointestinal and allergic reactions. The adverse effects of concurrent ifosfamide and mesna include urinary tract and renal toxicity. Although current FDA-approved labeling is limited to refractory germ cell testicular cancer, ifosfamide has also shown efficacy in the treatment of lymphoma, lung cancer, and sarcomas. Optimum dosage and scheduling remain to be determined; studies suggest that a fractionated dosage schedule provides antineoplastic activity with tolerable toxicity. Ifosfamide, used in combination with mesna for uroprotection, provides a useful therapeutic option for the management of patients with testicular cancer, soft tissue sarcomas, or high-grade malignant lymphomas.

Animals↗
PubMed1994

Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor.

PURPOSE: The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma. PATIENTS AND METHODS: From 1987 to 1991, 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1-2 years. Ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks. RESULTS: Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide. CONCLUSIONS: Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. Ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment.

Acute Kidney Injury↗
PubMed1996

The role of ifosfamide in the treatment of testicular and urothelial malignancies.

The activity of ifosfamide in genitourinary malignancies has been documented in testicular cancer and bladder cancer. The use of ifosfamide in germ cell tumors spans 20 years and has involved three distinct clinical settings: as a component of salvage therapy in cisplatin-resistant or recurrent disease, as part of initial therapy for patients with poor-risk disease, and as part of an ablative regimen for patients undergoing high-dose therapy with stem cell support. The use of ifosfamide in salvage therapy is well established, with approximately 40% to 50% of patients treated with a second-line ifosfamide-based regimen expected to achieve a complete response; however, only 25% of these patients will be long-term disease-free survivors. The drug's incorporation into standard-dose first-line regimens in patients with poor-risk disease has failed to improve the efficacy of therapy over standard, less toxic regimens. The value of ifosfamide as a component of high-dose salvage therapy with stem cell support in patients with refractory disease or of its increasing use as first-line therapy in patients with poor-risk features remains to be demonstrated. In urothelial carcinoma, data on the activity of ifosfamide are more sparse. Older trials in previously untreated patients in Japan and Egypt suggest an overall response rate of 30% to 40%, while a recent Eastern Cooperative Oncology Group trial in patients with prior chemotherapy reported a response rate of 20%. Ifosfamide has therefore been identified as one of six new active agents in urothelial cancer, and trials of combination regimens including ifosfamide are under way. The vinblastine/ifosfamide/gallium nitrate (VIG) combination was tested in a pilot study at Indiana University with a 67% overall response rate and in a confirmatory Eastern Cooperative Oncology Group phase II trial with a 56% response rate. Trials of ifosfamide plus paclitaxel with or without cisplatin are ongoing, but the role of ifosfamide in the routine therapy of urothelial malignancies remains to be determined.

Antineoplastic Combined Chemotherapy Protocols↗