Vinca Alkaloid Pharmacokinetics in the Context of a Physiologically‐Based Murine Model

Abstract

Vinca alkaloids are a class of molecule clinically used as cytotoxic chemotherapeutics, and exert their activity through mitotic disruption by preventing the polymerization of microtubules. While successfully used to treat a variety of cancer types, patients receiving these treatments remain at risk of toxic side‐effects due to significant variability observed in drug disposition. The objective of this study was to characterize the primary factors driving vinca alkaloid pharmacokinetics (PK), and develop a model capable of predicting PK based on alterations in these drivers. Physiologic sources of variability are known to include a wide range of reported values for CYP3A‐mediated metabolism and plasma protein binding, as well as a strong correlation between tissue uptake and tissue tubulin content. Additionally, vinca alkaloids are known substrates of ABCB1 (MDR1, PGP), which mediates drug efflux from tissues. To investigate dependence on these factors we initially developed a physiologically‐based pharmacokinetic (PBPK) model for vinblastine (VBL) dosed IV at 2 mg/kg in MDR1a −/− (KO) and MDR1a +/+ (WT) mice. An increase in VBL exposure was observed in all KO tissues compared to WT, particularly in brain which accumulated roughly 10‐fold more VBL over 6 hours. This is of particular importance as neurotoxicity is the most commonly reported dose‐limiting toxicity for vinca alkaloids. Additionally, excretion through biliary and renal routes were 6‐fold and 10‐fold lower, respectively, for both VBL and the active metabolite, desacetylVBL. Using known physiological and biochemical parameters the PBPK model was developed and validated for key organs involved in distribution, metabolism, and excretion of VBL in the MDR1a WT and KO mice. Through adjustment of relevant biochemical parameters the model was validated for vincristine (VCR) PK in MDR1a WT mice receiving the same 2mg/kg IV bolus dose, and used to simulate what VCR PK might look like in an MDR1a KO scenario. The validated PBPK model for VBL and VCR allows for investigation of PK based on alterations in measurable, physiologically‐relevant driving factors in murine models. Due to the pharmacologic similarities between molecules within the vinca alkaloid class, biochemical parameters can easily be adjusted to predict PK of vindesine and vinorelbine as well. Value of this model lies in its ability predict exposure in pre‐clinical studies involving vinca alkaloids, and provide insight into how exposure would be altered in combination therapy or gene knockout settings.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.