Disposition and metabolism of LY2603618, a Chk-1 inhibitor following intravenous administration in patients with advanced and/or metastatic solid tumors

Abstract

1. The disposition and metabolism of a Chk-1 inhibitor (LY2603618) was characterized following a 1-h intravenous administration of a single 250-mg dose of [¹⁴C]LY2603618 (50 µCi) to patients with advanced or metastatic solid tumors.

2. LY2603618 was well tolerated with no clinically significant adverse events. Study was limited to three patients due to challenges of conducting ADME studies in patients with advanced cancer. Plasma, urine and feces were analyzed for radioactivity, LY2603618 and metabolites. LY2603618 had a half-life of 10.5 h and was the most abundant entity in plasma, accounting for approximately 69% of total plasma radioactivity. The second most abundant metabolites, H2 and H5, accounted for <10% of total circulating radioactivity. The major route of clearance was via CYP450 metabolism. The mean total recovery of radioactivity was 83%, with approximately 72% of the radioactivity recovered in the feces and approximately 11% in the urine. LY2603618 represented approximately 6% and 3% of the administered dose in feces and urine, respectively.

3. A total of 12 metabolites were identified. In vitro phenotyping indicated that CYP3A4 was predominantly responsible for the metabolic clearance of LY2603618. Additionally, aldehyde oxidase was involved in the formation of a unique human and non-human primate metabolite, H5.

• Aldehyde oxidase
• cancer patients
• excretion
• mass balance
• radiolabelled study

Acknowledgements

The authors would like to thank Chad Hadden, Ph.D. for NMR support, Boris Czeskis, Ph.D., for synthesis of [¹⁴C] labelled LY2603618, Amy Burdan and Elizabeth Wagner for editorial support, and William Ehlhardt, Ph.D. for critical review and insightful comments.