Pediatric phase I trial and pharmacokinetic study of trimetrexate.
Trimetrexate, a new nonclassical antifolate, was evaluated in a phase I trial in children with refractory cancer including nine with acute leukemia and 21 with solid tumors. The drug was administered as an i.v. bolus injection weekly for three doses, and courses were repeated every 28 days. The dose ranged from 35 to 145 mg/m2. Thirty patients who received a total of 33 courses were evaluable for toxicity, including 19 who were evaluable for hematological toxicity. The maximally tolerated dose for patients with a solid tumor and leukemia was 110 mg/m2. The dose-limiting toxicities were myelosuppression, mucositis and a pruritic, diffuse maculopapular rash. Other side effects observed included transient, mild elevations of serum transaminases, mild nausea and vomiting, and a local phlebitis at the site of injection at higher dose levels. A single patient with delayed drug clearance had evidence of renal toxicity with a transient increase in serum creatinine. The pharmacokinetics of trimetrexate were studied in 25 patients over the entire dose range. There was considerable interpatient variability in total drug clearance (range 9.2 to 215 ml/min/m2) and half-life (2.1 to 20 h). There was a suggestion of a correlation between plasma concentration at 24 h and the development of hematological toxicity at the highest dose level. Trimetrexate was cleared primarily by biotransformation with renal clearance accounting for only 10% of total clearance. Two metabolites of trimetrexate which inhibit the enzyme dihydrofolate reductase were identified in the urine. One of these appears to be a glucuronide conjugate.
D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004341:Drug Evaluation; D005493:Folic Acid Antagonists / Q000009:adverse effects* / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D007223:Infant; D007700:Kinetics; D011799:Quinazolines / Q000009:adverse effects* / Q000378:metabolism; D016597:Trimetrexate
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005965:Glucuronates; D011799:Quinazolines; D016597:Trimetrexate