Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to...

Seventeen patients with low- or medium-risk gestational trophoblastic tumors (GTT) and one patient with a placental-site trophoblastic tumor were treated according to an 8-day schedule of low-dose methotrexate (LDMTX) alternating with citrovorum factor (CF). Plasma concentrations of methotrexate (MTX) were correlated with serum human chorionic gonadotropin (hCG) levels and clinical response. After an intramuscular dose of 50 mg, plasma MTX levels rose rapidly, reached a peak concentration of 5.8 x 10(-6) M/liter at 1 hour and persisted above 10(-6) M/liter normally considered inhibitory for DNA synthesis, for approximately 7 1/2 hours. Rapid plasma clearance followed with plasma levels reaching 5-7 x 10(-8) M/liter at the time of CF administration. At 48 hours, plasma MTX levels continued to exceed 10(-8) M/liter--the break point for the appearance of clinical toxicity due to MTX. In six of sixteen, or 38%, an initial rise in hCG levels was observed. Five of the seventeen patients, or 29%, and the one patient with PSTT developed MTX resistance. The administered dose (approximately 30 mg/M2) and plasma pharmacokinetics did not differ significantly between the tumors that responded and became resistant to MTX. The authors conclude that MTX resistance in GTT occurs as a result of impaired cell membrane uptake, gene amplification of dihydrofolate reductase, or both.