title: Are hepatic impairment studies necessary for therapeutic proteins?
abstract: OBJECTIVE
  This study assessed whether trials to investigate the effect of hepatic impairment on the pharmacokinetics of therapeutic proteins (TPs), which are conducted for small molecule drugs, are necessary.
  
  
  METHODS
  The product labeling for 91 TPs that have been approved by the US Food and Drug Administration were reviewed. A PubMed search was also conducted to identify completed studies that assessed the effect of hepatic impairment on the pharmacokinetics of TPs. Biologic License Applications were subsequently reviewed to gather further descriptions of the trials conducted in patients with hepatic impairment and data analyses.
  
  
  RESULTS
  No dedicated pharmacokinetics trials were conducted in patients with hepatic impairment for these approved TPs, but subgroup (n = 2 [2.2%]) or population (n = 5 [5.5%]) pharmacokinetic analyses were performed for 7 TPs. The pharmacokinetics of these proteins were not affected by the hepatic dysfunction, with the exception that the clearance of drotrecogin alfa seemed 25% higher in patients with hepatic impairment than in patients without hepatic impairment; however, no dose reduction was recommended. Thus, the effect of hepatic impairment on the pharmacokinetics of TPs is unclear based on the limited analyses completed to date.
  
  
  CONCLUSIONS
  A dedicated pharmacokinetics trial for TPs in patients with hepatic impairment is not necessary. Recognizing that the data are very limited, it would be important to continue collecting pharmacokinetic data of TP in patients with hepatic impairment and using population pharmacokinetic analyses to evaluate the effect of hepatic impairment on the pharmacokinetics of TP.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, Silver Spring, Maryland. Electronic address: jun.yang@fda.hhs.gov.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Stacy
authors.initials: S
authors.lastname: Shord
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Men
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000493:pharmacokinetics; D057487:Enzyme Therapy; D004798:Enzymes / Q000493:pharmacokinetics; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics; D008107:Liver Diseases / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D011506:Proteins / Q000493:pharmacokinetics*; D057127:Single-Chain Antibodies / Q000493:pharmacokinetics; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D004798:Enzymes; D000922:Immunotoxins; D011506:Proteins; D057127:Single-Chain Antibodies
keywords: hepatic impairment; pharmacokinetics; therapeutic proteins