title: Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Roswell Park Memorial Institute, Buffalo, NY 14263.
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: S F
authors.initials: SF
authors.lastname: Zakrzewski
authors.forename: W R
authors.initials: WR
authors.lastname: Greco
authors.forename: S
authors.initials: S
authors.lastname: Madajewicz
authors.forename: A
authors.initials: A
authors.lastname: Mittelman
authors.forename: J E
authors.initials: JE
authors.lastname: Pontes
authors.forename: C
authors.initials: C
authors.lastname: Karakousis
authors.forename: H
authors.initials: H
authors.lastname: Takita
authors.forename: A
authors.initials: A
authors.lastname: Proefrock
mesh_terms: 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
chemical_list: D000476:Alkanesulfonates; D005493:Folic Acid Antagonists; C055452:2,4-diamino-5-adamantyl-6-methyl-pyrimidine ethanesulfonate; D000218:Adamantane