Plasma levels of oral methotrexate in children receiving maintenance chemotherapy for acute lymphocytic leukemia

Lee, Soo Kwan; Song, Kih Yeon; Hwang, Young Hee; Lee, Young Hwan; Hah, Jeong Ok; Kim, Chun Dong

Abstract

This study was conducted to investigate plasma levels of oral methotrexate in rabbits and children receiving maintenance chemotherapy for acute lymphocytic leukemia. Eight New Zealand white rabbits, weighing 2kg in body weight, were divided into 3 groups and 5mg of methotrexate from 3 different manufactorying company was administered to the each group rabbits via nasogastric tube. Time to peak concentration ranged from 30 minutes to 3 hours (mean 1.2+/-0.9 hour)and the peak plasma concentration ranged from 0.08 micro M to 0.21micron M(mean 0.14+/-0.05 micronM)and area under the plasma concentration-time curve ranged from 0.6micron M.hr to 1.66micron M,hr (mean 1.06+/-0.36micronM,hr). There were no statistically significant difference in AUC of methotrexate in 3 groups, but interindividual variability in plasma levels of methotrexate was noted. Twelve patients with ALL who were receiving maintenance chemotherapy at pediatric department of Yeungnam University Hospital from August, 1988 to August, 1991 were studied. Plasma levels of oral methotrexale were monitored following an oral dose of 3.3 mg~10mg/m2 which was modified from recommended dose of 10 mg/m2 due to hepatotoxicity or myelosuppression. Time to peak concentration ranged from 30 minutes to 2 hours(mean 1.2+/-0.4 hour) and the peak plasma concentration ranged from 0.34 micron M to 0.8 micron M (mean 0.58+/-0.18micron M). The area under the plasma concentration-time curve ranged from 1.25micron M,hr to 3.79 micronM,hr (mean 2.71+/-0.84microM,hr)while standard area under the plasma concentration-time curve ranged from 0.13micronM, hr/mg/m2 to 0.54micronM, hr/mg/m2 (mean0.4+/-0.15micronM hr/mg/m2).Interindividual variability in plasma levels following an oral dose of methotrexate was noted. Peak plasma concentrations of study patients were all less than 1 micronM which is necessary for antileukemic effect of methotrexate in vitro. It seems to be necessary to increase the dose of methotrexate for all study patients, however optimal dose increment of methotrexate avoiding hepatotoxicity and myelosuppression need to be investigated further and measurement of plasma level of methotrexate is recommended when dose modification of methotrexate is made.