Vinblastine (VBL) is a vinca alkaloid‐class cytotoxic chemotherapeutic that causes microtubule disruption and is typically used to treat hematologic malignancies. VBL is characterized by a narrow therapeutic index, with key dose‐limiting toxicities being myelosuppression and neurotoxicity. Pharmacokinetics (PK) of VBL is primarily driven by ABCB1‐mediated efflux and CYP3A4 metabolism, creating potential for drug–drug interaction. To characterize sources of variability in VBL PK, we developed a physiologically based pharmacokinetic (PBPK) model in Mdr1a/b(−/−) knockout and wild‐type mice by incorporating key drivers of PK, including ABCB1 efflux, CYP3A4 metabolism, and tissue‐specific tubulin binding, and scaled this model to accurately simulate VBL PK in humans and pet dogs. To investigate the capability of the model to capture interindividual variability in clinical data, virtual populations of humans and pet dogs were generated through Monte Carlo simulation of physiologic and biochemical parameters and compared to the clinical PK data. This model provides a foundation for predictive modeling of VBL PK. The base PBPK model can be further improved with supplemental experimental data identifying drug–drug interactions, ABCB1 polymorphisms and expression, and other sources of physiologic or metabolic variability.
In cancer clinical trials hydroxychloroquine (HCQ) is the only approved autophagy inhibitor for use in treatment. Pharmacokinetic data from clinical trials comparing tumor vs. blood concentrations of HCQ suggest that there is a significant disconnect between drug levels within these compartments [Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH (2014) “Phase I Clinical Trial and Pharmacodynamic Evaluation of Combination Hydroxychloroquine and Doxorubicin Treatment in Pet Dogs Treated for Spontaneously Occurring Lymphoma Phase I Clinical Trial and Pharmacodynamic Evaluation of Combination Hydroxychloroquine.” Autophagy 10 (8): 1415–25]. Attempts to improve prediction of drug kinetics in these compartments have been made through development of individual patient‐focused physiologically‐based models, but these models fall short in predicting dynamic tumor cell‐specific intrinsic and extrinsic factors that dictate the amount of HCQ that sequesters within its ultimate pharmacodynamic target – the lysosome. Two factors intrinsic to tumor cells suggest that HCQ exposure should be predicted on a tumor‐by‐tumor basis. The first factor being basal levels of HCQ uptake drivers in the context of lysosomal burden, broken up into overall lysosomal volume and pH in a cell population. Different cell lines exhibit different pre‐exposure lysosomal burdens, modifying their overall initial exposure to HCQ both in vitro and in tumor‐bearing mice in vivo. Basal lysosomal burden is coupled to an adaptive response to HCQ exposure as well. This adaptive response is broken up into a short‐term component, driven primarily through lysosomal swelling, and a longer‐term component wherein TFEB‐activation induces biogenesis of functional lysosomes capable of sequestering HCQ. These intrinsic components result in a continual increase in cell uptake of HCQ over a 24‐hour period, split into rapid uptake within the short term (1st hour) and a slower, steadier uptake in the long term (1–24 hours). In addition, the main extrinsic factor that modulates HCQ exposure is extracellular pH. We observed a 5‐fold decrease in total cellular drug uptake and up to 10‐fold decrease in sensitivity to HCQ in media pH 6.8 vs. 7.4 across 4 cell lines. Combining these intrinsic and extrinsic factors we generate a cell‐based pharmacokinetic simulation model capable of predicting HCQ exposure to cell lines, and then translate it to next‐generation chloroquine derivatives through modification of compound‐specific physicochemical parameters. The power of this model is in its ability to account for dynamic systems within the tumor cell, giving a more accurate picture of how the tumor interacts with the drug, accounting for a major form of HCQ resistance through the non‐homogenous acidic tumor microenvironment in vivo, and pushing forward the development of next generation lysosomotropic autophagy inhibitors that may interact with the system similarly.
Support or Funding Information
National Cancer Institute [Grant R01CA190170 Therapeutic Targeti...
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