Wan-Yu Chu (1), A. Laura Nijstad (2), Lisa van der Heijden (1), Gareth J. Veal (3), Alwin D.R. Huitema (1,2,4), Thomas P.C. Dorlo (1)
(1) Netherlands Cancer Institute, Amsterdam, the Netherlands (2) University Medical Centre Utrecht, Utrecht, the Netherlands (3) Newcastle University, Newcastle upon Tyne, United Kingdom (4) Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Objectives:
A poor correlation between vincristine dose and plasma exposure has been observed, indicating nonlinear drug pharmacokinetics (PK) [1]. Several studies have suggested that platelets may play an important role in this characteristic, with around 70% of administered vinca alkaloids concentrated in platelets 0.5-2 hours post-dose, in both in vitro and in vivo studies [2–4]. In addition, binding between vinca alkaloids and platelets was shown to be reversible and saturable [2]. As platelets possess a well-defined system of microtubules, the theory that platelet-specific tubulins are more favorable to interact with vinca alkaloids was proposed [2,5]. A previous physiologically based pharmacokinetic (PBPK) study of vincristine implied a more extensive vincristine distribution in young children and assumed a 5-fold greater tissue tubulin expression in young children than in adults [6].
We hypothesized that platelet-binding is a possible determinant of vincristine distribution, and that differences in platelet binding capacity might explain the greater vincristine distribution found in children. The objective of this study was to evaluate above mechanistic hypotheses using a PBPK modeling approach.
Methods:
PK-Sim® and MoBi® (version 9.0) were applied for PBPK model development. Vincristine plasma concentrations and patient platelet counts used for model optimization and evaluation originated from 2 published PK studies [5,7], a dataset from Newcastle University (UK), and an ongoing prospective observational study that assesses PK of cytostatic agents in pediatric oncology (PINOCCHIO-study).
For adult PBPK model development, a 3-step simulation approach was performed to ensure the model represented biological plausibility. Firstly, the metabolism and elimination of vincristine by CYP3A4, CYP3A5 and P-glycoprotein (P-gp) were implemented. Secondly, specific binding of vincristine to tissue tubulin, which was previously suggested to be major determinant of vincristine disposition, was included [6]. Lastly, platelets were implemented as dummy protein binding partners expressed only in the blood cell compartment, to describe the uptake of vincristine by platelets. The final adult PBPK model was scaled to pediatric populations following the conventional PBPK model development workflow [8]. To understand the impact of platelet count on vincristine PK properties in adults and children, simulations were categorized into low, normal (150-450*109/L), and high platelets groups, and the PK parameters in different groups were analyzed by box whisker plots.
Results:
Vincristine PK data from 13 adults administered 2 mg vincristine were available for adult PBPK model optimization and evaluation. Data from 5 adolescents (13-15 years) given 2 mg vincristine, and 12 young children (2-10 years) given 1.5 mg/m2vincristine, were used for pediatric PBPK model optimization and evaluation.
For adults, the initial model included reactions of CYP3A4, CYP3A5 and P-gp underpredicted vincristine distribution. The subsequent model, which involved tissue tubulin-binding, required an optimal tubulin reference concentration that was 8-fold higher than literature values [9,10]. Therefore, this model was regarded physiologically implausible and strengthened the theory of more extensive vincristine platelet uptake. The final adult PBPK model with platelet-binding implemented provided an adequate description of the observed data, with an optimal tissue tubulin reference concentration of 1.35 µM and vincristine binding capacity of 0.0015 µmol/109platelets, both of which were consistent with literature values [9–12].
The PBPK models scaled from adults well described observed data in adolescents; however, once again underpredicted vincristine distribution in young children. An increase in both vincristine binding capacity in platelets and tissue tubulin concentration by 2-fold in young children, were implemented and resulted in adequate prediction of the PK data in young children.
Conclusions:
PBPK model simulations strengthened our hypothesis highlighting platelet-binding as a key determinant of vincristine distribution and indicated a relevant impact of platelet count on vincristine exposure, especially in the first few hours after administration. This study also confirmed a more extensive vincristine distribution in young children, which suggests a higher tubulin expression in this population.
References:
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Reference: PAGE 29 (2021) Abstr 9885 [www.page-meeting.org/?abstract=9885]
Poster: Drug/Disease Modelling - Oncology