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Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
The pharmacokinetics of ALKERAN after oral administration has been extensively studied in adult patients. Plasma melphalan levels are highly variable after oral dosing, both with respect to the time of the first appearance of melphalan in plasma (range approximately 0 to 6 hours) and to the peak plasma concentration (Cmax) (range 70 to 4,000 ng/mL, depending upon the dose) achieved. These results may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Five patients were studied after both oral and intravenous (IV) dosing with 0.6 mg/kg as a single bolus dose by each route. The areas under the plasma concentration-time curves (AUC) after oral administration averaged 61% ± 26% (± standard deviation [SD]; range 25% to 89%) of those following IV administration. In 18 patients given a single oral dose of 0.6 mg/kg of ALKERAN, the terminal elimination plasma half-life (t½) of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 to 0.25 mg/kg of ALKERAN, Cmax and AUC, when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respectively. Elimination phase t½ in these patients was approximately 1 hour and the median tmax was 1 hour.
One study using universally labeled 14C-melphalan, found substantially less radioactivity in the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV administration, the pattern of label recovery was similar, with the majority being recovered in the first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug (rather than just radiolabel) was determined, the melphalan half-disappearance time was 67 minutes.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major binding protein, while α1-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a significant positive correlation between the elimination rate constant for melphalan and renal function and a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve.
Last reviewed on RxList: 11/16/2016
This monograph has been modified to include the generic and brand name in many instances.
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