Amifostine

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Abstract
Amifostine (WR-2721) was originally developed as a radioprotective agent. In animals, it protects normal tissues from the damaging effects of irradiation and, as shown in more recent studies, of several cytotoxic agents. Protection of tumours is generally reduced compared with that of normal tissues in animals, suggesting that amifostine may increase the therapeutic window of cytotoxic therapies. Clinical data concerning amifostine suggest that cytotoxic chemotherapy-induced haematological toxicity and cisplatin-induced neurotoxicity, nephrotoxicity and ototoxicity are decreased upon administration of amifostine prior to cytotoxic drugs. Similarly, amifostine reduces damage to normal tissues caused by radiotherapy. Available data show that this protection is achieved without adversely affecting tumour response or patient survival. In 1 large trial, the reduction in cyclophosphamide- and cisplatin-related toxicities manifested as a decrease in the incidence and severity of neutropeniarelated fever and sepsis and in the number of patients with ovarian cancer who discontinued therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced nephro- and neurotoxicity were reduced. Increased doses of cytotoxic therapy have also been administered when amifostine was given prior to therapy, which may increase tumour response. The predominant adverse effects associated with amifostine are hypotension, nausea and vomiting, somnolence and sneezing. Thus, amifostine is likely to be a useful adjuvant to the treatment of patients with malignancy, particularly those receiving cyclophosphamide plus cisplatin. Although the pharmacodynamic properties of amifostine (WR-2721) have been investigated in animals, few human data are available. In animal models, amifostine is selectively dephosphorylated to WR-1065 which is absorbed by normal tissue and not tumour cells. In animals receiving cytotoxic chemotherapy, the efficacy of amifostine varied depending on the time between administration of each agent. Protection of normal tissues was greatest when amifostine was administered 5 or 30 minutes prior to cisplatin or carboplatin. In general, amifostine protected against haematological damage caused by carboplatin, carmustine, chlormethine, cisplatin, cyclophosphamide, fluorouracil or melphalan in mice. Cisplatin-induced nephrotoxicity and melphalan-induced gastrointestinal damage were also reduced by administration of amifostine. In vitro or animal studies assessing the effects of amifostine on carboplatin, cisplatin, cyclophosphamide or fluorouracil generally demonstrated a lack of tumour protection. Injection of amifostine protects against both early and late irradiation-induced injuries in a number of animal models. Maximum radioprotection results when amifostine is administered 30 to 60 minutes before irradiation. Degree of protection varies for different tissues, and in many tissues is reduced when a lower dose of irradiation or fractionated irradiation is administered. Mortality following irradiation was also reduced by amifostine. Radioprotection of tumour cells appears to be reduced compared with that of normal tissues and varied according to the method of irradiation, the type and size of the tumour and the assay endpoint. Gastrointestinal or haematopoietic radioprotection is enhanced, compared with monotherapy, when amifostine is administered in conjunction with several other agents, including recombinant granulocyte colony-stimulating factor. In contrast, an outcome between that seen with monotherapy with amifostine and the radiosensitiser misonidazole resulted when these agents were both administered prior to irradiation. Amifostine reduced or completely abolished the sensitising effect of misonidazole on tumours. In animals, amifostine therapy also reduced the incidence of irradiation-induced carcinogenesis or mutagenesis and generally did not potentiate, or significantly reduced, irradiation-induced metastases. Mutagenesis in bleomycin-, chlormethine-, cisplatin- or cyclophosphamide-treated mice was also reduced by amifostine. Dose-dependent hypocalcaemia resulted after administration of amifostine to humans. Reports in small numbers of (or individual) patients indicate that amifostine reduces serum calcium levels and urinary excretion of cyclic adenosine monophosphate. Amifostine is not orally active. When administered intravenously as a 15-minute infusion of 740 or 910 mg/m2 to patients with cancer, mean maximum plasma amifostine concentrations of 0.1 and 0.235 mmol/L, respectively, were achieved. The drug is rapidly cleared from the plasma compartment (clearance of 2.17 L/min) and has a short distribution half-life of about 0.9 minutes when administered as a bolus dose or 15-minute intravenous infusion. Thus, it has a low potential for drug interactions, as >90% of the drug is cleared from the plasma 10 minutes after administration. Amifostine does not appear to undergo appreciable protein binding in patients and is distributed heterogeneously to, and within, various tissues in mice and rats. In vitro analysis shows that amifostine is rapidly metabolised by alkaline phosphatase to the active metabolite WR-1065 and an inorganic phosphate. Further metabolism results in only a small proportion (about 6% in total) of a bolus dose or 15-minute infusion of amifostine being renally excreted by patients as unchanged drug or primary metabolites. In patients, amifostine has saturable kinetics and dose-dependent clearance. In most clinical trials, amifostine was infused 15 to 30 minutes prior to antineoplastic therapy at a dose of 740 to 910 mg/m2 (before cytotoxic chemotherapy) or lower (before irradiation). In patients receiving amifostine, no tumour protective effects or reductions in the efficacy of radiotherapy or cytotoxic chemotherapy were noted. Amifostine had no adverse effect on survival in those studies which assessed the effect of the drug on this parameter. The incidence and/or severity of cisplatin-, cyclophosphamide- and/or mitomycin-induced haematological toxicity was reduced in patients treated with amifostine in most clinical trials. Reductions in cisplatin-induced nephrotoxicity, neurotoxicity and ototoxicity were also reported in 1 large randomised trial. Protection manifest as a reduction in the incidence and duration of neutropenia-related fever and sepsis and/or days in hospital or days receiving antibacterial agents because of these effects. In addition, fewer amifostine-treated patients discontinued therapy before completion of a scheduled number of treatment cycles. An increase in the maximum tolerated dose of carboplatin was possible in 11 patients with advanced malignancies treated with amifostine, compared with historical controls. In a comparative trial, addition of amifostine to carboplatin therapy resulted in a reduced time to platelet recovery, although other haematological parameters were not significantly different after carboplatin alone or with amifostine. Amifostine reduced the incidence of late irradiation-induced damage to normal tissues, although it appeared to be less effective against early damage as shown in a comparative study of 98 patients with adenocarcinoma of the rectum. Protection of normal tissues was also demonstrated in 2 double-blind placebo-controlled studies conducted in patients with cancer of the head and neck or abdomen and pelvis. The severity and frequency of haematological toxicity produced by radiotherapy was also decreased by amifostine therapy. The faster return to baseline white blood cell counts in amifostine recipients suggested that the drug may improve progenitor cell survival after irradiation. In contrast to these positive findings, addition of amifostine to radiotherapy was ineffective in 7 patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia and offered no advantages over irradiation alone in a retrospective analysis of 83 patients with carcinoma of the uterine cervix. In patients receiving cytotoxic chemotherapy plus radiotherapy, amifostine reduced the incidence of haematological toxicity, irradiation-induced mucosal damage and cisplatin-induced ototoxicity, but not nephrotoxicity, and increased response rates compared with historical controls. The most common adverse effects of amifostine were emesis, hypotension, somnolence and sneezing in patients who received single or multiple doses of the drug. However, addition of antiemetics to treatment reduces the incidence of emesis. Amifostine was better tolerated when administered over 15 minutes compared with a constant infusion rate of about 14 to 20 mg/m2/min. Emesis, hypotension and somnolence were more common with higher drug doses, and in a phase 1 trial, emesis and somnolence were experienced significantly more frequently by women than men. Other less common adverse effects include a metallic taste, a flushed feeling, malaise, hypocalcaemia, hiccups, chills and idiosyncratic reactions including fever and/or rash. The initial recommended dose of amifostine is 910 mg/m2, administered over 15 minutes and started at most 30 minutes before administration of antineoplastic agents given by short infusion. Monitoring of arterial blood pressure is necessary during infusion of amifostine. Treatment should be interrupted if systolic blood pressure significantly decreases from baseline, but can be continued if blood pressure returns to baseline levels within 5 minutes and the patient remains asymptomatic. Amifostine 740 mg/m2 should be used for subsequent treatment cycles if the full drug dose cannot be administered. In a single dose-ranging study, children tolerated amifostine doses of up to 2700 mg/m2 when administered as a 15-minute infusion. Amifostine therapy requires coadministration of antiemetic therapy and, if necessary, calcium supplementation. Serum calcium levels should be monitored in patients at risk of hypocalcaemia. Amifostine has not be adequately evaluated in the elderly or in patients with renal or hepatic impairment.