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At least 19 recordsLinked to original sources
PubMed1990

Fractionated ifosfamide therapy produces a time-dependent increase in ifosfamide metabolism.

1. Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2. A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half-life of ifosfamide from 7.2 (2.8-14.2) h on day 1 to 4.6 (2.3-7.7) h on day 5 (P less than 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31-148) ml min-1 on day 1 to 115 (52-381) ml min-1 on day 5 (P less than 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1. 3. There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6-105) nmol nor nitrogen mustard equivalents ml-1 h to 52 (13-238) nmol nor nitrogen mustard equivalents ml-1 h on day 5. 4. During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3-16.2) ml min-1 compared with 5.7 (1.3-15.3) ml min-1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9-141.2) ml min-1 and 132.6 (54.6-149.5) ml min-1 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1986

Comparative studies on biological activity of /+/R and /-/S enantiomers of cyclophosphamide and ifosfamide. II. Antiproliferative activity of cyclophosphamide and ifosfamide enantiomers.

The present studies on antiproliferative activity of cyclophosphamide and ifosfamide /+/R and /-/S enantiomers followed the earlier described differences in their antitumour activity. P-388 leukemic cells in LCFU (Leukemic Colony Forming Units) assay and Lewis lung cells in experimental metastasis assay were used as models of tumour cells. Bone marrow stem cells were applied as models of normal proliferating cells in NCFU-(Normal Colony Forming Units) and RPNCFU (Rapidly Proliferating Normal Colony Forming Units) tests. In all four models /-/S enantiomers exerted higher antiproliferative effect, than their counterparts. Antiproliferative activity of /+/RS cyclophosphamide and ifosfamide appeared to be exactly intermediate between /+/R and /-/S forms. These data, precisely differentiating the effect of /+/R, /-/S and / +/- /RS forms, confirmed the earlier described, higher antitumour effect of /-/S enantiomers of cyclophosphamide and ifosfamide.

Animals↗
PubMed1988

Disposition of ifosfamide in patients receiving ifosfamide infusion therapy for the treatment of cervical carcinoma.

The disposition of ifosfamide was investigated in nine patients receiving a total of 23 72-h infusions. There was no linear relationship between steady-state plasma concentrations and either vomiting or CNS toxicity. The steady-state plasma concentrations were reproducible within patients, but there was a wide variation between patients. The progress of the disease did not affect the disposition of ifosfamide.

Female↗
PubMed1989

[Treatment of hormonal refractory adenocarcinoma of the prostate with ifosfamide (IFM) and the combination of vincristine ifosfamide and peplomycin (VIP)].

Nineteen patients with hormonal refractory adenocarcinoma of the prostate were treated with ifosfamide (IFM) and the combination of vincristine, ifosfamide and peplomycin (VIP). Nine of them were treated with IFM, and nine with VIP, and one with IFM and also VIP. In the case of the IFM therapy, the over-all response rate was 0% by the Karnofsky's category of response, 20% by the response criteria of Shida et al., 50% by the National Prostatic Cancer Project (NPCP) criteria, and 0% by the response criteria of Koyama and Saito. In the case of the VIP therapy, the over-all response rate was 30% by the Karnofsky's category, 30% by the response criteria of Shida et al., 70% by the NPCP criteria and 20% by the response criteria of Koyama and Saitoh. The one-year survival rates of these patients treated with IFM and VIP were both about 20%. Only one patient treated with VIP therapy showed a partial response. Therefore, a more effective regimen for hormonal refractory adenocarcinoma of the prostate must be developed.

Adenocarcinoma↗
PubMed1986

Comparative studies on biological activity of /+/R and /-/S enantiomers of cyclophosphamide and ifosfamide. I. Antitumour effect of cyclophosphamide and ifosfamide enantiomers.

The differences in antitumour effect of /+/R and /-/S enantiomers of both cyclophosphamide and ifosfamide were detected. In the case of ifosfamide in all five tested tumour models (Leukemia L1210, P388, Lewis lung carcinoma, 16/C mammary adenocarcinoma and B16 melanoma) the /-/S form exerted not only higher antitumour effects than /+/R form, but revealed higher therapeutic indices as well. The same appeared to be true for /-/S enantiomer of cyclophosphamide in three models of solid tumours. In L1210 and P-388 ascitic leukemia models /+/R and /-/S cyclophosphamide exerted the same antitumour effect.

Animals↗
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↗
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↗
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↗
PubMed1991

Ifosfamide pharmacokinetics.

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

Administration, Oral↗
PubMed1991

Metabolism and pharmacokinetics of oral and intravenous ifosfamide.

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

Acetaldehyde↗
PubMed1989

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

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

Adult↗
PubMed1989

Potentiation of ifosfamide toxicity by chlordiazepoxide, diazepam and oxazepam.

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

Animals↗
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↗
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↗
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↗