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Case Reports
. 2022 Oct;39(10):2487-2495.
doi: 10.1007/s11095-022-03364-1. Epub 2022 Aug 19.

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

A Laura Nijstad  1   2   3 , Wan-Yu Chu  4 , Evelien de Vos-Kerkhof  5 , Catherine F Enters-Weijnen  5   6 , Mirjam E van de Velde  7 , Gertjan J L Kaspers  5   7 , Shelby Barnett  8 , Gareth J Veal  8 , Arief Lalmohamed  9   10 , C Michel Zwaan  5   11 , Alwin D R Huitema  9   12   4
Affiliations
Case Reports

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

A Laura Nijstad et al. Pharm Res. 2022 Oct.

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.

Keywords: oncology; pediatric; pharmacokinetics; population pharmacokinetics.

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Conflict of interest statement

There are no conflicts of interests to declare.

Figures

Fig. 1
Fig. 1
Graphical representation of the final model for vincristine. kon is driven by the amount of vincristine, bound to tubulin (A(bound)) and Bmax. Bmax Maximal binding capacity; CL Clearance; koff Dissociation rate constant; kon Association rate constant; Q Intercompartmental clearance; Vc Vincristine central compartment; Vp Vincristine peripheral compartment.
Fig. 2
Fig. 2
Vincristine clearance (solid grey line), maximum binding capacity (solid black line) and absolute vincristine dose for three different infant dosing regimen over age: A. All ages: 1.5 mg/m2 (dashed line). B. Children < 6 months: 50% of BSA dose (0.75 mg/m2); Children 6–11 months: 75% of BSA dose (1.125 mg/m2); Children ≥ 12 months: 1.5 mg/m2 (dashdotted line). C. Children < 10 kg: 0.05 mg/kg/day; Children ≥ 10 kg: 1.5 mg/m2 (dotted line).
See this image and copyright information in PMC

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