Open AccessSemi‐Mechanism‐Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib
Author(s) -
Lu T,
Wang B,
Gao Y,
Dresser M,
Graham RA,
Jin JY
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12039
Subject(s) - vismodegib , pharmacokinetics , pharmacology , hedgehog signaling pathway , population , medicine , oncology , basal cell carcinoma , basal (medicine) , cancer research , chemistry , biochemistry , basal cell , signal transduction , environmental health , insulin
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 predominantly explained by the range of AAG level. The impact of AAG on unbound concentration was clinically insignificant. Various approaches were evaluated for model validation. The semi‐mechanism‐based PopPK model described herein provided insightful information on the nonlinear PK and has been utilized for various clinical applications.