Pediatric phase I trial and pharmacokinetic study of trimetrexate.
Pediatric phase I trial and pharmacokinetic study of trimetrexate.
复制标题
曲美曲沙的儿科 I 期试验和药代动力学研究。
作者：
F. Balis;Ramesh Patel;Enrique Luks;K. Doherty;J. Holcenberg;Charlotte Tan;Gregory H. Reaman;Jean B. Belasco;Lawrence J. Ettinger;S. Zimm;D. Poplack
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.
甲氨蝶呤耐药白血病细胞体外对非经典抗叶酸药三甲曲沙（TMQ，2,4-二氨基-5-甲基-6-[(3,4,5-三甲氧基苯胺基)甲基]喹唑啉）的摄取和功效。
影响因子：
5.8
作者：
Kamen,BA;Eibl,B;Cashmore,A;Bertino,J
通讯作者：
Bertino,J