AMIFOSTINE

AMIFOSTINE — amifostine injection, powder, lyophilized, for solution
Sun Pharmaceutical Industries Limited

DESCRIPTION

Amifostine for injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl) amino] ethanethiol dihydrogen phosphate (ester) and has the following structural formula:

structure

Amifostine is a white crystalline powder, which is freely soluble in water. Its molecular formula is C5 H15 N2 O3 PS and it has a molecular weight of 214.22.
Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.

CLINICAL PHARMACOLOGY

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. The ability of 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 cisplatin.

Pharmacokinetics:

Clinical pharmacokinetic studies show that 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 Amifostine remains in the plasma 6 minutes after drug administration. 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 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 to 8 minutes after intravenous infusion of Amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on 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 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 withAmifostine 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 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 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 *
*
Creatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976; 16:31-41.
Amifostine+CP CP p-value(2-sided)
All Patients16/122 (13%)36/120 (30%)0.001
First Cohort10/6320/580.018
Second Cohort6/5916/620.026
TABLE 2 NCI Toxicity Grades of Serum Magnesium Levels for Each Patient’s Last Cycle of Therapy
*
Based on 2-sided Mantel-Haenszel Chi-Square statistic.
NCI-CTC Grade:(mEq/L) 0 >1.4 1 ≤1.4 to >1.1 2 ≤1.1 to >0.8 3 ≤0.8 to >0.5 4 ≤0.5p-value *
All Patients Amifostine+CP CP927313183705010.001
First Cohort Amifostine+CP CP4935108360301 0.017
Second Cohort Amifostine+CP CP43383100102000.012

In the randomized ovarian cancer study, 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 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
Amifostine +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)
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