Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies.

This pharmacokinetic study examined the relationship between methotrexate (MTX) dose and drug concentrations in blood and cerebrospinal fluid (CSF) during repeated 24 hr infusions. Two regimens were used: an intermediate dose (ID) of 0.5 g/m2 (7 patients, 23 cycles) and a high dose (HD) of 2.5 g/m2 (8 patients, 39 cycles). Inter-patient variability in the drug concentration was apparent in serum and CSF for both doses. The dispersion was particularly wide in CSF for HD MTX. Considering median values, serum and CSF MTX were linked to dose escalation. Individual CSF/serum drug ratios were not modified by the dose (1.1% for ID MTX versus 1.4% for HD MTX). A potentially cytotoxic drug level in CSF (10(-6) M) was never obtained for ID MTX cycles, but was achieved in 44% of HD MTX cycles: for HD MTX, this corresponded to 88% of patients (7/8). Total body clearance did not modify the degree of CSF MTX passage. A positive, significant correlation (r = 0.62, P less than 0.05) was observed for ID MTX between individual serum and CSF MTX; no such relationship was seen with HD MTX. Individual cycle-to-cycle variations in the MTX concentration were particularly marked in CSF and for HD MTX, without strict concordance with blood levels.