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

Richard A. Graham, Bert L. Lum, Sravanthi Cheeti, Jin Yan Jin, Karin Jorga, Daniel D. Von Hoff, Charles M. Rudin, Josina C. Reddy, Jennifer A. Low, Patricia M. LoRusso

Research output: Contribution to journalArticle

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 (K D =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.

Original languageEnglish (US)
Pages (from-to)2512-2520
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011

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  • Cancer Research
  • Oncology

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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. / Graham, Richard A.; Lum, Bert L.; Cheeti, Sravanthi; Jin, Jin Yan; Jorga, Karin; Von Hoff, Daniel D.; Rudin, Charles M.; Reddy, Josina C.; Low, Jennifer A.; LoRusso, Patricia M.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2512-2520.

Research output: Contribution to journalArticle

Graham, Richard A. ; Lum, Bert L. ; Cheeti, Sravanthi ; Jin, Jin Yan ; Jorga, Karin ; Von Hoff, Daniel D. ; Rudin, Charles M. ; Reddy, Josina C. ; Low, Jennifer A. ; LoRusso, Patricia M. / 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. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2512-2520.
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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 (K D =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.",
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T2 - The role of alpha-1-acid glycoprotein binding

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AU - Lum, Bert L.

AU - Cheeti, Sravanthi

AU - Jin, Jin Yan

AU - Jorga, Karin

AU - Von Hoff, Daniel D.

AU - Rudin, Charles M.

AU - Reddy, Josina C.

AU - Low, Jennifer A.

AU - LoRusso, Patricia M.

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