Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
A F RatliffB A Kamen

Abstract

Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT. Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration. Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability ...Continue Reading

Citations

Sep 5, 2007·Cancer Chemotherapy and Pharmacology·Peter D ColeBarton A Kamen
Aug 13, 2002·Anti-cancer Drugs·Paul KremerHannsjörg Sinn
Sep 20, 2005·Cancer Chemotherapy and Pharmacology·Peter D ColeBarton A Kamen
Sep 29, 2009·Cancer Chemotherapy and Pharmacology·Robin E Norris, Peter C Adamson
May 13, 2010·Drug Metabolism and Pharmacokinetics·Yuichi Uwai, Kikuo Iwamoto
Mar 10, 2012·Expert Opinion on Investigational Drugs·Caitriona RyanAlan Menter
Apr 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Suman MalempatiUNKNOWN Children's Oncology Group
Jul 25, 2013·Cancer Chemotherapy and Pharmacology·Michele VisentinI David Goldman
Nov 22, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Peter D ColeBarton A Kamen

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