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KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: Evaluation of the Absorption, Distribution, Metabolism and Excretion of a single oral 300 mg dose of [14C]KAE609 in healthy male subjects

Huskey, Su-Er and Zhu, Chunqi and Fredenhagen, Andreas and Kuehnoel, Juergen and Luneau, Alexandre and Jian, Zhigang and Yang, Ziping and Miao, Zhuang and Yang, Fan and Jain, Jay Prakash and Sunkara, Gangadhar and Mangold, James and Stein, Daniel (2016) KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: Evaluation of the Absorption, Distribution, Metabolism and Excretion of a single oral 300 mg dose of [14C]KAE609 in healthy male subjects. Drug Metabolism and disposition, DMD 44 (5). pp. 672-682. ISSN 1521-009X

Abstract

KAE609 is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. The absorption, distribution, metabolism and excretion of KAE609 was investigated after oral administration of [14C]KAE609 in healthy subjects. Following oral administration , KAE609 was the major radioactive component in plasma, ( ~76% of the total radioactivity ); M23 was the major circulating oxidative metabolite, (~12% of the total radioactivity ). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for ~3-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized such that KAE609 accounted for ~32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported yellowish semen discoloration after dosing in prior studies; therefore semen samples were collected once from each subject to further investigate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the conclusion that this yellow colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biological matrices albeit at low levels. All 19 recombinant human CYP enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was utilized to generate sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in human are summarized herein and M23 is the major metabolite in plasma and excreta.

Item Type: Article
Keywords: human ADME, KAE609, spiroindolone, malaria, plasma, exposure, metabolite, excretion, metabolism
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27743

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