A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children

Abstract

Abstract Background Vincristine, a chemotherapeutic agent that extensively binds to β-tubulin, is commonly dosed at 1.4–2.0 mg/m2 capped at 2 mg. For infants, doses vary from 0.025–0.05 mg/kg or 50–80% of the mg/m2 dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. Methods 206 patients (0.04–33.9 years; 25 patients < 1 years), receiving vincristine, with 1297 plasma concentrations were included. Semi-mechanistic population pharmacokinetic analyses were performed using non-linear mixed effects modelling. Results A three-compartment model, with one saturable compartment resembling saturable binding to β-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to β-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6–33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2–70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23–6.46) and of the peripheral compartment as 400 L (95%CI 357–463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479–0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. Interpretation A decrease of vincristine β-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine.