468P - Phase I study to compare safety and pharmacokinetics of afatinib, an oral irreversible ErbB family blocker, in non-cancer subjects with hepatic impa...

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Clinical research
Basic Scientific Principles
Presenter David Schnell
Authors D. Schnell1, S. Buschke2, H. Fuchs3, R. Göldner4, M. Uttenreuther-Fischer5, P. Stopfer6, S. Wind2, A. Halabi7, R. Koenen1
  • 1Translational Medicine, Boehringer Ingelheim, Biberach/DE
  • 2Pharmacokinetics, Boehringer Ingelheim, Biberach/DE
  • 3Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim, Biberach/DE
  • 4Statistics, Boehringer Ingelheim, Biberach/DE
  • 5Clinical Development & Medical Affairs, Boehringer Ingelheim, Biberach/DE
  • 6Clinical Pharmacokinetics/pharmacodynamics, Boehringer Ingelheim, Biberach/DE
  • 7Medical Director, CRS Clinical Research Services Kiel GmbH, Kiel/DE



Afatinib (BIBW 2992) is an oral, irreversible ErbB Family Blocker. It was found to be mainly excreted via faeces and is highly protein bound. To define the impact of different degrees of hepatic impairment (HI) on the pharmacokinetics (PK) and safety of afatinib, a dedicated Phase I trial was conducted.

Table: 468P

50 mg afatinib, mild HI (N = 8) 50 mg afatinib, HV matched to mild HI (N = 8) 50 mg afatinib, moderate HI (N = 8) 50 mg afatinib, HV matched to moderate HI (N = 8)
Parameter Unit gMean gCV [%] gMean gCV [%] gMean gCV [%] gMean gCV [%]
AUC0-∞ [ng*h/mL] 886 53.7 956 22.7 934 31.0 985 32.3
Cmax [ng/mL] 33.7 51.7 30.7 33.7 39.5 40.1 31.1 46.0
AUC0-tz [ng*h/mL] 842 50.8 930 22.5 904 31.4 956 33.3


This single-dose, open-label, dose-escalation study in a matched group design included male or female subjects with HI (mild: Child Pugh A, score 5 or 6; moderate: Child Pugh B, score 7 to 9) and healthy volunteers (HV) matched to the HI subjects based on age, weight, sex and creatinine clearance. Dose escalation of afatinib from 30 to 50 mg was performed depending on tolerability and PK. Plasma and urine sampling was performed for up to 240 hours (h) and 72 h after afatinib administration, respectively. Primary endpoints were comparison of AUC0-∞ and Cmax of afatinib between subjects with HI and matched healthy subjects. For all other parameters, descriptive statistics were calculated. Additionally, blood samples were drawn to determine in vitro plasma protein binding of afatinib.


Thirty-five subjects entered the trial: 3 subjects with mild HI received single-dose 30 mg afatinib and 32 subjects received single-dose 50 mg afatinib. Tolerability of afatinib was good, with 6/35 subjects showing AEs, which were related to afatinib in 3/35 subjects. Main PK parameters are given in Table 1. After a single dose of 50 mg, PK parameters were similar between patients with HI and their matched HV controls.


Mild and moderate HI had no influence on the PK and tolerability of a single dose of 50 mg afatinib. Table 1: Comparison of main PK parameters after single-dose administration of 50 mg afatinib.


D. Schnell: Employee of SocraMetrics / Boehringer Ingelheim.

S. Buschke: Employee of Boehringer Ingelheim.

H. Fuchs: Employee of Boehringer Ingelheim.

R. Göldner: Employee of Boehringer Ingelheim.

M. Uttenreuther-Fischer: Employee of Boehringer Ingelheim.

P. Stopfer: Employee of Boehringer Ingelheim.

S. Wind: Employee of Boehringer Ingelheim.

A. Halabi: Employee of CRS Clinical Research Services / Boehringer Ingelheim.

R. Koenen: Employee of Boehringer Ingelheim.