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Ethyol

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Ethyol

CLINICAL PHARMACOLOGY

ETHYOL (amifostine) is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of ETHYOL (amifostine) to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.

Pharmacokinetics: Clinical pharmacokinetic studies show that ETHYOL (amifostine) is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of ETHYOL (amifostine) remains in the plasma 6 minutes after drug administration. ETHYOL (amifostine) is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of ETHYOL (amifostine) , renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of ETHYOL (amifostine) . Pretreatment with dexamethasone or metoclopramide has no effect on ETHYOL (amifostine) pharmacokinetics.

Clinical Studies

Chemotherapy for Ovarian Cancer

A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without ETHYOL (amifostine) pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. In both cohorts, after multiple cycles of chemotherapy, pretreatment with ETHYOL (amifostine) significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥ 40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine ( > 1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of ETHYOL (amifostine) was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of ETHYOL (amifostine) in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.

TABLE 1: Proportion of Patients with ≥ 40% Reduction in Calculated Creatinine Clearance*

  ETHYOL+CP CP p-value
(2-sided)
All Patients 16/122 (13%) 36/120 (30%) 0.001
First Cohort 10/63 20/58 0.018
Second Cohort 6/59 16/62 0.026
*Creatinine clearance values were calculated using the Cockcroft-Gaultformula, Nephron1976; 16:31-41.

TABLE 2: NCI Toxicity Grades of Serum Magnesium Levels for Each Patient's Last Cycle of Therapy

NCI-CTC Grade: (mEq/L) 0 1 2 3 4 p-value*
>1.4 ≤ 1.4->1.1 ≤ 1.1->0.8 ≤ = 0.8->0.5 ≤ 0.5
All Patients   0.001
  ETHYOL+CP 92 13 3 0 0
  CP 73 18 7 5 1
First Cohort   0.017
  ETHYOL+CP 49 10 3 0 0
  CP 35 8 6 3 1
Second Cohort   0.012
  ETHYOL+CP 43 3 0 0 0
  CP 38 10 1 2 0
* Based on 2-sided Mantel-Haenszel Chi-Square statistic.

In the randomized ovarian cancer study, ETHYOL (amifostine) had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the ETHYOL (amifostine) and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.

TABLE 3: Comparison of Principal Efficacy Findings

  ETHYOL +CP CP
Complete pathologic tumor response rate
21.3% 15.8%
Time to progression (months)
  Median (▒ 95% CI) 15.8 (13.2, 25.1) 18.1 (12.5, 20.4)
  Mean (▒ Std error) 19.8 (▒1.04) 19.1 (▒1.58)
  Hazard ratio (95% Confidence Interval) .98 (.64,1.4)
Survival (months)
  Median (▒ 95% CI) 31.3 (28.3, 38.2) 31.8 (26.3, 39.8)
  Mean (▒ Std error) 33.7 (▒2.03) 34.3 (▒2.04)
  Hazard ratio (95% Confidence Interval) .97 (.69,1.32)

Radiotherapy for Head and Neck Cancer

A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without ETHYOL (amifostine) , administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving ETHYOL (amifostine) (TABLE 4).

TABLE 4: Incidence of Grade 2 or Higher Xerostomia (RTOG criteria)

  ETHYOL +RT RT p-value
Acute
( ≤ 90 days from start of radiation)
51% (75/148) 78% (120/153) p<0.0001
Latea
(9-12 months post radiation)
35% (36/103) 57% (63/111) p=0.0016
a Based on the number of patients for whom actual data were available.

At one year following radiation, whole saliva collection following radiation showed that more patients given ETHYOL (amifostine) produced > 0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received ETHYOL (amifostine) (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.

In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).

TABLE 5: Comparison of Principal Efficacy Findings at 1 Year

  ETHYOL +RT RT
Locoregional Control Ratea 76.1% 75.0%
  Hazard Ratiob 1.013
  95% Confidence Interval (0.671, 1.530)
Disease-Free Survival Ratea 74.6% 70.4%
  Hazard Ratiob 1.035
  95% Confidence Interval (0.702, 1.528)
Overall Survival Ratea 89.4% 82.4%
  Hazard Ratiob 1.585
  95% Confidence Interval (0.961, 2.613)
a1 year rates estimated using Kaplan-Meier method
bHazard ratio >1.0 is in favor of the ETHYOL (amifostine) + RT arm

Last reviewed on RxList: 8/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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