n 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 the drug 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.
Arm 2: IV melphalan 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.
Doses of melphalan were adjusted according to the following criteria:
Table 1. Criteria for Dosage Adjustment in a Randomized Clinical Trial WBC/mm3
Platelets
Percent of Full Dose
≥4,000
≥100,000
100
≥3,000
≥75,000
75
≥2,000
≥50,000
50
<2,000
<50,000
0
One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the IV arm (P<0.04). Response rates at week 22 are shown in the following table:
Table 2. Response Rates at Week 22 Initial Arm
eva luable
Patients
Responders
n (%)
P
Oral melphalan
100
44 (44%)
P>0.2
IV melphalan
195
74 (38%)
Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.
Severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was ≥30 mg/dL. The rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment.
Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.
INDICATIONS AND USAGE
ALKERAN for Injection is indicated for the palliative treatment of patients with mult |
