Pharmacokineties of vincristine monotherapy in childhood acute lymphoblastic leukemia

We studied vincristine pharmacokinetics in 70 children newly diagnosed with acute lymphoblastic leukemia, after a single dose of vincristine as monotherapy. Vincristine plasma concentrations were measured by HPLC analysis. A two-compartment, first-order pharmacokinetic model was fitted to the data by maximum a posteriori parameter estimation. In this group of children pharmacokinetic factors were highly variable: median (25th and 75th percentiles) total body clearance, 228 (128-360) mL.min(-1).m(-1); elimination half-life, 1001 (737-1325) min; apparent volume of distribution at steady state 262 (158-469) L/m(2). Vincristine clearance was substantially slower than has been reported previously for children receiving vincristine in combination with steroids as part of combination chemotherapy (median clearance, 228 mL.min(-1).m(-1) versus mean clearance, 381 and 482 mL.min(-1).m(-2), respectively). Steroids are known as inducers of vincristine-metabolizing cytochrome P-450 3A4 enzymes. The absence of steroids during our study appears to be the most likely explanation for this difference. Furthermore, we found that vincristine clearance was faster in patients with hyperdiploid (>50 chromosomes) than in patients with diploid or hyperdiploid (46-50 chromosomes) leukemic blasts.