title: Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects.
abstract: BACKGROUND
  While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity.
  
  
  CONCLUSIONS
  This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing.
  
  
  OBJECTIVE
  Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses.
  
  
  METHODS
  Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry.
  
  
  RESULTS
  Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.
  
  
  CONCLUSIONS
  Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. graham.richard@gene.com
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Marie T
authors.initials: MT
authors.lastname: Borin
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Dawn
authors.initials: D
authors.lastname: Colburn
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
authors.forename: Vikram
authors.initials: V
authors.lastname: Malhi
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002853:Chromatography, Liquid; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D017711:Nonlinear Dynamics; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001798:Blood Proteins; C538724:HhAntag691; D011725:Pyridines