Physiologically Based Pharmacokinetic Modeling of Central Nervous System Pharmacokinetics of CDK4/6 Inhibitors to Guide Selection of Drug and Dosing Regimen for Brain Cancer Treatment.

ABSTRACT: A better understanding of the human central nervous system (CNS) pharmacokinetics is critical to the selection of the right drug and refinement of dosing regimen for more effective treatment of primary and metastatic brain cancer. Using the physiologically-based pharmacokinetic (PBPK) modeling approach, we systematically compared the CNS pharmacokinetics of three cyclin D-cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (ribociclib, palbociclib, and abemaciclib) in patients with cancer. A PBPK model platform was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration to the in vitro half-maximal inhibitory concentration (IC₅₀ ) for CDK4/6 inhibition,

SUBMITTER: Li J 

PROVIDER: S-EPMC7854954 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature