Vincristine pharmacokinetics after repetitive dosing in children

Purpose: We studied vincristine disposition after 169 weekly i.v. bolus inj ections in 32 children with acute lymphoblastic leukemia, non-Hodgkin lymph oma, or Wilms' tumor. The aim of the study was to determine intrapatient an d interpatient variability in vincristine disposition and demographic, clin ical, and biochemical characteristics influencing this variability. Methods : Vincristine plasma concentrations were measured by a high-performance liq uid chromatography assay with electrochemical detection. A limited sampling strategy was used based on a bayesian parameter estimation algorithm that is part of the ADAPT II software package. A two-compartment, first-order mo del was fitted to the data, and pharmacokinetic parameters were calculated from the model using the ADAPT II software. For statistical analysis, analy sis of variance (ANOVA), t test, simple and multiple regression analysis, a nd non-parametric or robust equivalents were used. Results: Results showed a large intrapatient and interpatient variability in distribution half-life , elimination half-life, total body clearance, apparent volume of distribut ion at steady state, and area under the concentration-time curve. Intrapati ent variability was significantly smaller than interpatient variability for all these parameters except distribution half-life. The diagnosis or treat ment protocol turned out to be the most predictive characteristic; leukemia and non-Hodgkin lymphoma patients had a significantly higher total body cl earance than Wilms' tumor patients. Conclusions: We conclude that both intr apatient and interpatient variability in vincristine pharmacokinetics is la rge in pediatric cancer patients and that variability, although significant ly influenced by diagnosis, largely remains unpredictable.