Metabolic disposition of AZD8931, an oral equipotent inhibitor of EGFR, HER2 and HER3 signalling, in rat, dog and man. (December 2014)

• Record Type: Journal Article
• Authors: Ballard, Peter; Swaisland, Helen C.; Malone, Michael D.; Sarda, Sunil; Ghiorghiu, Serban; Wilbraham, Darren
• Is Part Of: Xenobiotica. Volume 44:Number 12(2014:Dec.)
• Page Start: 1083
• Page End: 1098
• Publication Date: 2014-12
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.938257
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. This series of studies in rats, dogs and humans (Clinicaltrials.gov identifier: NCT01284595) investigated the pharmacokinetics, tissue distribution, metabolism and excretion of the EGFR, HER2 and HER3 signalling inhibitor AZD8931.</p> <p>2. Single oral or intravenous doses of 2-(4-[4-(3-chloro-2-fluoro[U-<sup>14</sup>C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate ([<sup>14</sup>C]-AZD8931) were administered.</p> <p>3. AZD8931 absorption was rapid in all species. Following [<sup>14</sup>C]-AZD8931 administration to rats, radioactivity was widely and rapidly distributed, with the highest levels in organs of metabolism and excretion (gastrointestinal tract, liver). Following oral and intravenous [<sup>14</sup>C]-AZD8931 administration, excretion of radioactivity by all species occurred predominantly via the bile into faeces, with <5% of the dose being eliminated in urine. In all species, AZD8931 was principally cleared by metabolism. The major route of metabolism was hydroxylation and <italic>O</italic>-demethylation in rat, and aryl ring oxidation in dog. Metabolism of AZD8931 in humans was attributed to three pathways; oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation.</p> <p>4. AZD8931 is largely cleared by metabolism in the rat, dog and human. Excretory profiles indicate that there are no unique human metabolites.</p> </abstract>