title: Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule.
abstract: Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.
authors.affiliation: Department of Medicine, Vermont Regional Cancer Center, Burlington 05401.
authors.forename: J A
authors.initials: JA
authors.lastname: Stewart
authors.forename: J J
authors.initials: JJ
authors.lastname: McCormack
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: J B
authors.initials: JB
authors.lastname: Low
authors.forename: J D
authors.initials: JD
authors.lastname: Roberts
authors.forename: A
authors.initials: A
authors.lastname: Blow
authors.forename: L R
authors.initials: LR
authors.lastname: Whitfield
authors.forename: L D
authors.initials: LD
authors.lastname: Haugh
authors.forename: W R
authors.initials: WR
authors.lastname: Grove
authors.forename: A J
authors.initials: AJ
authors.lastname: Lopez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000187:drug effects; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012867:Skin / Q000187:drug effects; D016597:Trimetrexate
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D016597:Trimetrexate