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Cancer Chemother Pharmacol. 2012 Apr;69(4):1051-61. doi: 10.1007/s00280-011-1803-9. Epub 2011 Dec 27.

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers.

Author information

1
Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse, 88400 Biberach an der Riss, Germany. Peter.Stopfer@boehringer-ingelheim.com

Abstract

PURPOSE:

To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers.

METHODS:

In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [(14)C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [(14)C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography.

RESULTS:

[(14)C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [(14)C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [(14)C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated.

CONCLUSIONS:

Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.

PMID:
22200729
DOI:
10.1007/s00280-011-1803-9
[Indexed for MEDLINE]

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