title: Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment.
abstract: OBJECTIVE
  Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib.
  
  
  METHODS
  This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C max and AUC0-∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of afatinib.
  
  
  RESULTS
  Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC0-∞ was 92.6% (90% CI 68.0-126.3%) and Cmax was 109.5% (90% CI 82.7-144.9%) for subjects with mild hepatic impairment, and 94.9% (90% CI 72.3-124.5%) and 126.9% (90% CI 86.0-187.2%), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90% CI included 100%. Afatinib was generally well tolerated with no serious adverse events reported.
  
  
  CONCLUSIONS
  Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany, david.schnell@boehringer-ingelheim.com.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.forename: Susanne
authors.initials: S
authors.lastname: Buschke
authors.forename: Holger
authors.initials: H
authors.lastname: Fuchs
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gansser
authors.forename: Rainer-Georg
authors.initials: RG
authors.lastname: Goeldner
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: Sven
authors.initials: S
authors.lastname: Wind
authors.forename: Marc
authors.initials: M
authors.lastname: Petersen-Sylla
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Koenen
mesh_terms: D000293:Adolescent; D000328:Adult; D000077716:Afatinib; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000077716:Afatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human