Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.
A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I--daily x5; II--24-h continuous infusion. In schedule I, doses of 10-90 mg/m2 per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m2 were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m2 per day for 5 days or 192 mg/m2 by continuous infusion for 24 h. Pharmacokinetic studies indicated a beta-phase plasma half-life of 12.4-24 h and a large and variable volume of distribution.
Creaven
P J
PJ
Department of Clinical Pharmacology and Therapeutics, Roswell Park Memorial Institute, Buffalo, NY 14263.
Zakrzewski
S F
SF
Greco
W R
WR
Madajewicz
S
S
Mittelman
A
A
Pontes
J E
JE
Karakousis
C
C
Takita
H
H
Proefrock
A
A
D000218:Adamantane / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000368:Aged; D000476:Alkanesulfonates / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002621:Chemistry; D004341:Drug Evaluation; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008433:Mathematics; D008838:Microcomputers; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012984:Software
D000476:Alkanesulfonates; D005493:Folic Acid Antagonists; C055452:2,4-diamino-5-adamantyl-6-methyl-pyrimidine ethanesulfonate; D000218:Adamantane