Semi-Mechanism-Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib.

ABSTRACT: Vismodegib, approved for the treatment of advanced basal cell carcinoma, has shown unique pharmacokinetic (PK) nonlinearity and binding to α1-acid glycoprotein (AAG) in humans. A semi-mechanism-based population pharmacokinetic (PopPK) model was developed from a meta-dataset of 225 subjects enrolled in five clinical studies to quantitatively describe the clinical PK of vismodegib and identify sources of interindividual variability. Total and unbound vismodegib were analyzed simultaneously, together with time-varying AAG data. The PK of vismodegib was adequately described by a one-compartment model with first-order absorption, first-order elimination of unbound drug, and saturable binding to AAG with fast-equilibrium. The variability of total vismodegib concentration at steady-state was pred

SUBMITTER: Lu T 

PROVIDER: S-EPMC4716579 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature