Identification, Characterization, and Implications of Species-Dependent Plasma Protein Binding for the Oral Hedgehog Pathway Inhibitor Vismodegib (GDC-0449)

Abstract

Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is ≥95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug concentrations and α-1-acid glycoprotein (AAG) in a phase I study. Biophysical and cellular techniques have been used to reveal that vismodegib strongly binds to human AAG (K(D) = 13 μM) and binds albumin with lower affinity (K(D) = 120 μM). Additionally, binding to rat AAG is reduced ∼20-fold relative to human, whereas the binding affinity to rat and human albumin was similar. Molecular docking studies reveal the reason for the signficiant species dependence on binding. These data highlight the utility of biophysical techniques in creating a comprehensive picture of protein binding across species.

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

“…Vismodegib fraction unbound is believed to be dependent on AAG saturation which occurs as the vismodegib concentration increases with repeated daily dosing, resulting in establishment of equilibrium with HSA (17). Fraction unbound remains low due to binding to HSA which serves as a low affinity, high capacity drugbinding protein relative to AAG due to its high level in plasma ( Supplementary Fig.…”

“…Furthermore, vismodegib levels were strongly correlated with alpha 1-acid glycoprotein (AAG) levels, showing parallel fluctuations of AAG and total drug over time and consistently low unbound drug levels. This unique PK profile was shown to be due to high-affinity reversible binding to AAG and binding to albumin (17), in addition to nonlinear absorption and slow metabolic elimination (18). A mechanism-based conceptual PK model was developed to provide a quantitative description of the observed vismodegib phase I data (18).…”

Self-Assembly Drugs: From Micelles to Nanomedicine

“…Evaluation of binding of vismodebig (a selective Hedgehog pathway inhibitor) with human and rat AAGs and albumins have confirmed that binding is rapidly and completely reversible. The data suggest that as compound enters the bloodstream, it will preferentially bind to available binding sites on AAG rather than albumin [107]. ITC studies further demonstrate that quinacrine can serve as a targeting ligand for specific delivery of additional therapeutic molecules or imaging agents to the receptoroverexpressing cancer cells implicated in breast and prostate cancers.…”

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

“…Vismodegib was optimized for suitable potency; selectivity; and absorption, distribution, metabolism, and excretion properties Wong et al, 2009;Castanedo et al, 2010). Its unique absorption, distribution, metabolism, and excretion properties contribute to vismodegib's prolonged circulating half-life (Wong et al, 2010;Giannetti et al, 2011;Graham et al, 2011aGraham et al, , 2012). Here we report on studies to determine the mechanism of formation of three ring-opened metabolites formed as a result of metabolism of the pyridine moiety.…”