title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Genentech Inc, South San Francisco, California 94080, USA. graham.richard@gene.com
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Cheeti
authors.forename: Jin Yan
authors.initials: JY
authors.lastname: Jin
authors.forename: Karin
authors.initials: K
authors.lastname: Jorga
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Josina C
authors.initials: JC
authors.lastname: Reddy
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001667:Binding, Competitive; D001682:Biological Availability; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012709:Serum Albumin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D009961:Orosomucoid; D011725:Pyridines; D012709:Serum Albumin