Pharmacokinetic monitoring of high-dose methotrexate

Abstract

The administration of high-dose methotrexate (HDMTX) with leucovorin rescue carries with it a risk of severe toxicity which may be fatal. In the present study, patients with a 24-h serum concentration of 5 x10- M and an elimination half-life (T1/2) of 3.5 h during the first 24 h after the infusion were considered at low risk for toxicity and received conventional lowdose leucovorin rescue. Patients not meeting these criteria were considered at high risk for toxicity and received an escalated and extended course of leucovorin. The low-risk criteria were met following 109 of 114 HDMTX infusions administered to 30 patients. None of these patients developed toxicity with low-dose leucovorin. The 24-h serum concentration and the t1/2 exceeded the low-risk criteria following five HDMTX infusions administered to three patients. In two of these three patients leucovorin was continued until the MTX concentration was 10-8 M (168–265 h) and no toxicity developed. The third high-risk patient discontinued his leucovorin 11 days prior to a MTX serum concentration 10-8 M and developed moderate toxicity. Clinical features present in the three high-risk patients, which were not present in the low-risk group, included a pleural effusion in one patient and gastrointestinal obstruction in the other two patients. The identification of 3/30 high-risk patients in the present study was consistent with a historical control group in which 6/65 patients developed severe toxicity. These data indicate that patients meeting the criteria described herein are at low risk to develop toxicity with conventional leucovorin rescue and that high-risk patients may be identified early enough to reduce or prevent toxicity.