title: Some considerations on the predictions of pharmacokinetic alterations in subjects with liver disease.
abstract: BACKGROUND
  The liver is one of the most important organs responsible for the elimination of xenobiotics and there is considerable regulatory pressure to characterize the in vivo pharmacokinetic (PK) changes in subjects with liver disease (LD). Despite this, predictions of the potential effect of LD on the PK of compounds present several limitations.
  
  
  METHODS
  We examined a list of marketed drugs with the aim to identify compound PK characteristics potentially correlated to the extent of PK changes in LD.
  
  
  CONCLUSIONS
  Extensive renal elimination (> 40%) was the only predictor of the lack of significant changes in PK in subjects with LD. Parameters related to hepatic extraction (extraction ratio, clearance, oral clearance) were only weakly correlated to PK changes. The interplay of the effects of liver impairment on bioavailability and systemic clearance may prevent compound characteristics predictive of large increases of systemic exposure in subjects with LD compared to healthy subjects from being highlighted. A wider knowledge-base and a deeper scientific understanding may be needed to obtain predictive assessments of PK alterations in these conditions. The use of multivariate analysis can provide a stimulus for a more detailed mechanistic understanding of the absorption and disposition changes to be expected in LD.
authors.affiliation: Janssen PRD, Clinical Pharmacology , 920 Route 202 South, Raritan, NJ 08869 , USA MGonza02@its.jnj.com.
authors.forename: Martha
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Italo
authors.initials: I
authors.lastname: Poggesi
mesh_terms: D001682:Biological Availability; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology*; D008954:Models, Biological; D015999:Multivariate Analysis; D010599:Pharmacokinetics; D015262:Xenobiotics / Q000493:pharmacokinetics*
chemical_list: D015262:Xenobiotics
keywords: Child–Pugh; dosing recommendations; hepatic impairment; multivariate analysis; pharmacokinetic determinants; physiology-based pharmacokinetic modeling