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01.04.2012 | Original Article

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

verfasst von: Peter Stopfer, Kristell Marzin, Hans Narjes, Dietmar Gansser, Mehdi Shahidi, Martina Uttereuther-Fischer, Thomas Ebner

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2012

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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 [¹⁴C]-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. [¹⁴C]-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

[¹⁴C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [¹⁴C]-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 [¹⁴C]-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.

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Titel: Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
verfasst von: Peter Stopfer
Kristell Marzin
Hans Narjes
Dietmar Gansser
Mehdi Shahidi
Martina Uttereuther-Fischer
Thomas Ebner
Publikationsdatum: 01.04.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1803-9

Springer Medizin

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers