Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding

Abstract

Purpose In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. Experimental Design Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance–based microsensor, and AAG levels by ELISA. Results A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R2 = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (KD = 13 μmol/L) and human serum albumin less strongly (KD = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. Conclusions GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.

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

“…Unbound vismodegib was measured in ultrafiltrate from plasma samples that underwent equilibrium dialysis (18). AAG levels in serum were determined by immunonephelometry using a standard clinical laboratory procedure.…”

“…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).…”

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

“…A semimechanistic conceptual PK simulation approach has been used previously to explore multiple hypotheses for the observed nonlinear PK of vismodegib as well as the relationship between total vismodegib concentration and AAG level 17, 20. Based on various model structures adapted from the conceptual PK model and the clinical PK data from phase I/II trials (unbound, total vismodegib, and AAG), the PopPK model was successfully developed to understand the PK characteristics of vismodegib, which was critical for dose and schedule optimization.…”

“…The conceptual PK model17, 20 incorporated zero‐order absorption with a limited absorption window, fast equilibrium binding to both AAG and albumin (low capacity and high affinity for AAG; high capacity and low affinity for albumin), and slow intrinsic clearance of unbound vismodegib. The current PopPK model was modified by simplifying absorption (first‐order absorption) and protein binding components (saturable binding to AAG only).…”

“…Previously, a semimechanistic conceptual PK simulation approach was used to explore multiple hypotheses for the nonlinear PK of vismodegib 17, 20. The conceptual PK model incorporated three main hypotheses: zero‐order absorption with a limited absorption window, fast equilibrium binding to both AAG and albumin (low capacity and high affinity for AAG; high capacity and low affinity for albumin), and slow intrinsic clearance of unbound vismodegib.…”