Clinical and pharmacologic reappraisal of dichloromethotrexate.
Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.
Hantel
A
A
Johns Hopkins Oncology Center, Baltimore, MD 21205.
Rowinsky
E K
EK
Noe
D A
DA
McGuire
W P
WP
Grochow
L B
LB
Vito
B L
BL
Ettinger
D S
DS
Donehower
R C
RC
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C004763:3',5'-dichloromethotrexate; D008727:Methotrexate