TY - JOUR
T1 - Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors
AU - LoRusso, Patricia M.
AU - Jimeno, Antonio
AU - Dy, Grace
AU - Adjei, Alex
AU - Berlin, Jordan
AU - Leichman, Lawrence
AU - Low, Jennifer A.
AU - Colburn, Dawn
AU - Chang, Ilsung
AU - Cheeti, Sravanthi
AU - Jin, Jin Y.
AU - Graham, Richard A.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens:QD (n = 23), TIW (n = 22), orQW(n = 22) for up to 42 days after an 11-day loading phase (150 mgQD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.
AB - Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens:QD (n = 23), TIW (n = 22), orQW(n = 22) for up to 42 days after an 11-day loading phase (150 mgQD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.
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U2 - 10.1158/1078-0432.CCR-11-0972
DO - 10.1158/1078-0432.CCR-11-0972
M3 - Article
C2 - 21753154
AN - SCOPUS:80052475002
SN - 1078-0432
VL - 17
SP - 5774
EP - 5782
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -