title: Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). 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.
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Grace
authors.initials: G
authors.lastname: Dy
authors.forename: Alex
authors.initials: A
authors.lastname: Adjei
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Leichman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Dawn
authors.initials: D
authors.lastname: Colburn
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Cheeti
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
mesh_terms: D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines