Melphalan - How It Works
Clinical pharmacology details from the US FDA-approved label: how Melphalan works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
CLINICAL PHARMACOLOGY 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 N 7 position of guanine.
Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
Pharmacokinetics Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively.
Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m 2 ) were observed.
One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course.
Mean (±SD) peak melphalan plasma concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m 2 were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.
The steady-state volume of distribution of melphalan is 0.5 L/kg.
Penetration into cerebrospinal fluid (CSF) is low.
The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%).
Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α 1 -acid glycoprotein accounts 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 study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.
Clinical Trial A randomized trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma.
As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after week 22 are impossible to make.
Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks.
Melphalan doses in each arm were: Arm 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.
Pharmacokinetics
Pharmacokinetics Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m 2 ) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m 2 were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively. The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α 1 -acid glycoprotein accounts 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