Abstract
A preliminary methotrexate (MTX) kinetic evaluation following administration of an IV bolus (test-dose) allowed individualization of high-dose infusions (HD-MTX). This approach combined with therapeutic drug monitoring was found to have good performance over a large scale of predicted steady-state levels (Css) (10-5 to 10-4 M over 24 to 36 h) corresponding to 17 to 650 mg/h deliveries (root mean squared error: rmse (precision) = 1.54 x 10-5 M (21.4 %) and mean error: me (bias) = 0.043 x 10-5 M (NS)).
However a significative (p< 0.05) but rather low over-estimation of dosage (me = 7.38 x 10-5 M (14.8 %)) associated to a decrease in the prediction precision (rmse = 13.3 x 10-5 M (26.6 %)) occured in 5 x 10-4 M predicted Css over 8 h (970 to 1970 mg/h deliveries). However in a number of cases (6 out of 29) important deviations from predicted Css occured, implying the need to stop the infusion before 8 h.
These results indicated that MTX pharmacokinetics was linear from low test-dose bolus injections to high-dose infusions. This allowed dosage predictions based upon preliminary estimation of MTX clearance and associated to therapeutic drug monitoring during and following infusion.
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