Vincristine disposition in children with acute lymphoblastic leukemia

Abstract

Vincristine (VCR) has been widely used to treat childhood malignancies for over thirty years, but its plasma disposition has not yet been well-defined. Therefore, we conducted a pharmacokinetic study of VCR in 17 children with acute lymphoblastic leukemia (ALL) receiving the first dose of VCR. A new high-performance liquid chromatographic assay was used for the measurement of VCR in plasma. A two-compartment pharmacokinetic model was fit to the data by nonlinear least-squares regression. Estimated pharmacokinetic parameters were highly variable; mean (S.D.) volume of distribution at steady-state was 360 (176) L.m-2; total body clearance was 431 (238) ml.min-1.m-2, and elimination half-life was 823 (390) min. These results were compared to data from eight adults with lung cancer. Mean volume of distribution in adults and children were similar, but VCR clearance was significantly larger in children (P = 0.01), resulting in a significantly longer elimination half-life in the adults (P < 0.01). We conclude that administration of a standard dosage of VCR to children with ALL results in a highly variable systemic drug exposure, which may have implications for the oncolytic effect and/or toxicity in individual patients. Comparison of data from children and adults suggests that VCR elimination rate is a function of age; this could account for more severe neurotoxicity in older patients. However, it cannot be excluded that differences between the children and adults may be due to other variables than age. Future studies should focus on the possible influence of multidrug resistance modulating agents on VCR pharmacokinetics and on pharmacokinetic-pharmacodynamic relationships in individual patients.

Pharmacokinetics of Vincristine Monotherapy in Childhood Acute Lymphoblastic Leukemia

“…Blood sampling was scheduled before and 10, 30, 180, and 1440 min after vincristine administration. This schedule was designed with the optimal sampling design module of the ADAPT II software package (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA, U.S.A.) (30,35). Heparinized blood samples (4 mL) were drawn from a different site from the vincristine injection and immediately placed on ice.…”

“…A two-compartment, firstorder pharmacokinetic model was fitted to the vincristine concentration data. Primary pharmacokinetic variables were estimated by maximum a posteriori parameter estimation with a Bayesian algorithm using the ADAPT II software package with priors from 32 previously studied patients (30,31,35,36). Factors of the variance model were fixed at a coefficient of 0.1 and an exponent of 2.0.…”

“…CL appeared to be faster in children than in adults (mean CL, 431 and 189 mL·min Ϫ1 ·m Ϫ2 , respectively) (29,30). Both intra-and interpatient variability turned out to be large in pediatric cancer patients (31).…”

Reversible vincristine‐related flaccid paralysis in a child with acute lymphoblastic leukemia

“…Severe (WHO 3/4) VCR related-neurotoxicity in ALL is described mainly in adults, in subjects carrying concomitant inherited neurologic disorders, in cases of high dosage administration or drug over dosage and is often irreversible or lethal [7][8][9]. None of these conditions was applicable to our pediatric patient in whom, the neuropathy was severe but resolved rapidly with an almost complete return of motor performance within 20 days.…”

Vincristine pharmacokinetics in children with down syndrome

“…The small number of samples per patients, typical for most pharmacokinetic studies in children, prompted us to use a limited sampling strategy for the analysis of pharmacokinetic data. We used a Bayesian approach with ''priors'' from previously studied non-DS patients [11]. We realize that for this study independent ''priors'' from a group of DS patients with an extensive sampling schedule would have been preferable, but obtaining such priors would hardly be feasible.…”