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 (R(2) = 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 (K(D) = 13 μmol/L) and human serum albumin less strongly (K(D) = 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.

Figure 1

Pharmacokinetics of GDC-0449 after single- and multiple-dose administration. Plasma concentrations of total (A) and unbound (B) GDC-0449 over time are shown after a single dose and after multiple daily doses (C, total; D, unbound). (For C and D, PK samples from a patient who discontinued from the study early were not collected after the initiation of multiple dosing.) Average steady-state concentrations of total (E) and unbound (F) GDC-0449 in all subjects in the 150, 270, 540, and 150 mg phase II formulation cohorts are also presented. In E and F, The line in the middle of the box represents the median, the top and bottom box limits represent the 25th and 75th percentiles, and the top and bottom bars represent 1.5 times the interquartile range.

Figure 2

The percentage of unbound GDC-0449 is low and consistent across the range of GDC-0449 concentrations achieved within the study.

Figure 3

Total GDC-0449 and AAG plasma concentrations are highly correlated. The scatter plot includes all data from each patient after day 21 of daily dosing and is reflective of steady-state conditions.

Figure 4

Concentration-time profiles in three representative patients (A), (B), and (C). Left y-axis reflects plasma concentration of total GDC-0449 and AAG, whereas right y-axis reflects serum concentration of HSA.

Figure 5

Mechanistic PK model and associated simulations. A, schematic depicting the physiologic processes that likely dictate GDC-0449 pharmacokinetics. The model assumes that the unbound drug and the drug–HSA binding complex are both available for binding to AAG in order to reproduce the strong correlation between GDC-0449 and AAG plasma concentrations. Unbound drug elimination from plasma is incorporated into the model as a first-order rate constant (k_el) via metabolism and/or parent excretion. Unbound drug can bind to and inhibit SMO activity, leading to blockade of hedgehog signaling at the target tumor site. The final model assumed that drug was absorbed from the GI tract into vasculature at a constant zero-order rate (k₀) due to limited solubility in the GI tract. In addition, drug can be absorbed only during a limited period of GI transit time (T₀), which limits its bioavailability, especially at higher doses and after multiple doses. Model simulations for total GDC-0449 (B), unbound GDC-0449 (C), and the correlation between GDC-0449 and AAG concentrations (D) are shown.