Pharmacokinetics (PK) of [14C]-BIBW 2992 after administration of a single dose of 15 mg [14C]-BIBW 2992 oral solution in healthy male volunteers

Abstract

14607 Background: BIBW 2992 is a novel oral, potent and irreversible inhibitor of EGFR and HER2. This study investigated the PKs and the mass balance of a single oral dose of [14C]-radiolabelled BIBW 2992 in healthy male volunteers. Safety and tolerability of BIBW 2992 were also investigated. Methods: This was a Phase I, open label, single dose study with [14C]-radiolabelled BIBW 2992 performed at one study centre in 8 healthy male subjects receiving one single dose of 15 mg of BIBW 2992 containing 2.25 MBq of [14C]-radiolabelled BIBW 2992. Observation period for the collection of samples of blood, urine and feces was at least 120 hours. Plasma and urine concentrations of BIBW 2992 were analyzed using high performance liquid chromatography coupled to tandem mass spectrometry. [14C]-radioactivity levels in plasma, whole blood, urine and feces were analyzed by Liquid Scintillation Counting methods. Results: The major route of elimination of total [14C]-radioactivity was found to be via feces (85.4%) with an overall recovery of [14C]-radioactivity of 89.5%. For BIBW 2992 as well as for [14C]-plasma and whole blood radioactivity, maximum plasma concentrations were reached around 6 hours after dosing. The gMean terminal half-life (t1/2) was 33.9 hours for BIBW 2992, 118 hours for [14C]-radioactivity in plasma and 195 hours for [14C]-radioactivity in whole blood. A relatively high apparent total body clearance (CL/F) for BIBW 2992 was determined. The gMean CL/F values for the [14C]- radioactivity in plasma and whole blood were low. BIBW 2992 as well as [14C]-radioactivity in plasma and in whole blood exhibited a high apparent volume of distribution (Vz/F) during the terminal phase. BIBW 2992 was generally tolerated with only mild adverse events of short duration (all CTCAE Grade 1) reported. Conclusions: BIBW 2992 was safe and well tolerated at a single dose of 15 mg. The major route of elimination of BIBW 2992 is via feces. The data suggest the presence of one or more metabolites of BIBW 2992 in plasma and in whole blood with a longer terminal half-life than BIBW 2992. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG