Administration Of Ifosfamide Research Articles

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.

Sequential Studies of Rat Urinary Bladder Epithelial Lesions Induced by Ifosfamide (Z4942)

Urinary bladder damage caused by ifosfamide in male F344 rats was studied by light microscopy and scanning electron microscopy. Ifosfamide was injected intraperitoneally at doses of 30, 60 and 120 mg. per kg. body weight, and rats were killed at several intervals following treatment. The changes in the epithelium observed by light microscopy and scanning electron microscopy following ifosfamide injection were compared to those observed following cyclophosphamide injection. Necrosis and exfoliation of the urinary bladder epithelium occurred after day 1 of ifosfamide treatment and were followed by regenerative hyperplasia. This hyperplasia was reversible. A dose response was evident in the number and size of lesions induced and the time of regeneration and repair. Scanning electron microscopy disclosed short, uniform microvilli on the luminal surface of cells during the early phases of hyperplasia. These microvilli persisted for only 1 day, from days 1 to 7, and days 1 to 12 respectively, following injection of 30, 60 and 120 mg. per kg. of ifosfamide. The hyperplastic lesions also contained cells with pleomorphic microvilli and ropy or leafy microridges on their surfaces. These findings after ifosfamide administration were similar to those reported to be induced in the urinary bladder by cyclophosphamide.

Chemotherapy of metastatic seminoma.

Response to chemotherapy and survival was retrospectively analyzed in 28 patients with bulky retroperitoneal and disseminated seminoma treated between 1977 and 1983. The median age was 41 years (range: 23-52). All patients had histological evidence of pure testicular seminoma, however, 14 patients revealed moderate increases of human beta-chorionic gonadotropin levels. Prior radiotherapy had been given to 9/28 (32%) patients. Treatment consisted of at least four courses of simultaneous or sequentially alternating therapy with cisplatin, vinblastine, bleomycin plus/minus adriamycin (PVB +/- A), administration of ifosfamide or combination therapy with ifosfamide/cisplatin (IFS/DDP) or ifosfamide/etoposide (IFS/ETP). Twenty-five of 28 patients (89%) achieved a complete (CR), and 3/28 patients a partial remission. Relapse occurred in 1/8 CR patients after adjuvant postchemotherapeutic irradiation, and in 1/11 patients without any further radiotherapy. So far, 23/28 patients (82%) are free of disease after a median follow-up of 28+ (14+----82+) months. Marked myelosuppression was observed in previously irradiated patients, mainly after PVB +/- A therapy. In two patients, transient nephrotoxicity developed after PVB and IFS/DDP, respectively. After PVB +/- A chemotherapy, three patients revealed polyneuropathy, paralytic subileus and bleomycin-induced pneumonitis, respectively. In conclusion, the present series suggests a high probability of continuous CR in even bulky retroperitoneal and widespread metastatic seminoma. So far, no definite conclusions can be made on the therapeutic superiority of one of the different chemotherapeutic regimens used. However, this preliminary experience suggests that the combination of ifosfamide and etoposide or cisplatin may prove less toxic than sequentially alternating or simultaneous PVB +/- A chemotherapy.

Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna: results of a clinical phase II-study with 151 patients

In a clinical phase II study 151 patients with refractory malignant diseases were treated with ifosfamide (60 mg/kg/day i.v. days 1-5, q 21-28 days). Altogether, 490 courses of treatment were given, 92 with conventional prophylactic measures (continuous infusion of 3-4 litre physiological saline plus alkalinization of the urine) and 398 with mesna prophylaxis (12 mg/kg i.v., 0, 4 and 8 h after administration of ifosfamide). The overall response rate (min. 25% tumor reduction) was 67/151 (44%) including four complete remissions in a fairly unfavourable patient group with testicular teratoma (39/87), soft tissue sarcoma (10/16), malignant melanoma (2/7), osteogenic sarcoma (3/6), Ewing's sarcoma (2/6), lymphoma and acute leukemia (5/7) or other histologies (6/22). The response rate in patients pretreated by cyclophosphamide containing regimen was 7/19 (36%) including one complete remission and one partial remission. Mesna was highly effective in reducing the frequency of hemorrhagic cystitis from 25/92 (27%) to 16/398 (4%) ifosfamide courses. The antitumor activity of ifosfamide in testicular cancer was not reduced by mesna. In conclusion, ifosfamide with the potent uroprotector mesna appears to compare favourably with the most active agents in the treatment of malignant diseases.

Ifosfamide in combination chemotherapy for sarcomas and testicular carcinomas

The efficacy of ifosfamide combination chemotherapy was studied in 164 patients, 94 with advanced testicular carcinoma and 70 with metastatic sarcoma. Ifosfamide was given at 40-60 mg/kg/day i.v. on five consecutive days every 3-4 weeks together with mesna prophylaxis with 8 mg/kg i.v. being used at 0, 4 and 8 h after ifosfamide administration. Of 70 sarcoma patients 57 were evaluable for response, of whom 49 had received prior chemotherapy. The overall response rate was 46% (26/57) including 3 complete (CR) and 14 partial remissions (PR). Ninety-four patients with germ cell tumours of the testis were treated. Of 16 seminoma patients 15 achieved CR or PR. Seventy-eight patients with nonseminomatous testicular cancer who had received previous chemotherapy were either treated with ifosfamide/etoposide (n = 63, remission rate: 30%) or ifosfamide/cisplatin (n = 15, CR + PR: 33%). These results indicate that ifosfamide alone or in combination is active in sarcomas, seminomas and teratomas and that further studies are warranted employing the drug in first-line regimens.

Randomised trial comparing sequential methotrexate (or 5-FU), vinblastine and ifosfamide to vincristine, adriamycin and ifosfamide in advanced lung cancer

A randomised trial has compared the sequential administration of ifosfamide (with its urinary antidote mesna) combined with methotrexate (or 5-FU in adenocarcinomas) and vinblastine (protocol I) or combined with adriamycin and vincristine (protocol II) in advanced lung cancer. In 29 evaluable cases the results were not influenced by the protocol nor by the histology of the tumors (oat cell v non-oat cell) or the clinical stage (limited v extensive). An overall response rate of 58.6% was obtained (100% in the oat cell and anaplastic carcinomas, 44% in adenocarcinomas, 50% in squamous cell carcinomas) with a clear prolongation of survival in responding groups, whatever the clinical stage.

Comparison of the cardiovascular actions of NSC-109,724 (ifosfamide) and cyclophosphamide

Abstract The iv administration of the alkylating agents NSC-109,724 (ifosfamide) or cyclophosphamide (75, 150 or 300 mg/kg) in anesthetized rhesus monkeys produced an immediate dose-dependent hypotension, bradycardia and a diminution in high-frequency, low-amplitude EEG wave activity. Histamine levels in blood were also found to be elevated. Ifosfamide appeared to be twice as potent as cyclophosphamide in causing cardiovascular alterations. The magnitude and duration of the cardiovascular responses after 150 mg/kg ifosfamide were attenuated by a 30 min pretreatment with either diphenhydramine (10 mg/kg), chlorpheniramine (5 mg/kg) or tripelennamine (6 mg/kg). Ifosfamide and cyclophosphamide (75, 150 or 300 mg) caused a dose-related decrease in force of contraction and heart rate in the isolated, blood-perfused, dog heart preparation. At each dose ifosfamide produced more pronounced and prolonged actions than cyclophosphamide. Pretreatment of the isolated heart with diphenhydramine (10 mg), chlorpheniramine (5 mg) or tripelennamine (6 mg) did not entirely prevent the initial depressant actions of 150 mg ifosfamide but did allow the rate and force to return to control levels in a shorter time. These experiments suggest that the hypotension and bradycardia observed after administration of ifosfamide, and to a lesser extent cyclophosphamide, may be due to a direct nonspecific cardiac depression in conjunction with possible histamine release.