TY - JOUR T1 - Biotransformation Pathways and Metabolite Profiles of Oral [14C]-Alisertib (MLN8237), an Investigational Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.087338 SP - dmd.119.087338 AU - Sandeepraj Pusalkar AU - Xiaofei Zhou AU - Yuexian Li AU - Lawrence Cohen AU - Jun Johnny Yang AU - Suresh K. Balani AU - Cindy Xia AU - Wen Chyi Shyu AU - Chuang Lu AU - Karthik Venkatakrishnan AU - Swapan K. Chowdhury Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/01/07/dmd.119.087338.abstract N2 - Alisertib (MLN8237) is an investigational, orally available, selective Aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematological malignancies. This metabolic profiling analysis was conducted as part of a broader phase 1 study evaluating mass balance, pharmacokinetics, metabolism, and routes of excretion of alisertib following a single 35 mg dose of [14C]-alisertib oral solution (~80 μCi) in three patients with advanced malignancies. On average, 87.8% and 2.7% of the administered dose was recovered in feces and urine, respectively, for a total recovery of 90.5% by 14 days post-dose. Unchanged [14C]-alisertib was the predominant drug-related component in plasma, followed by O-desmethyl alisertib (M2; 34.6% of total plasma radioactivity) and alisertib acyl glucuronide (M1; 12.0% of total plasma radioactivity). In urine, of the 2.7% of the dose excreted, unchanged [14C]-alisertib was a minor component, with M1 (0.84% of dose) and glucuronide conjugate of hydroxy alisertib (M9; 0.66% of dose) representing the primary drug-related components in urine. Hydroxy-alisertib (M3; 20.8% of the dose administered) and unchanged [14C]-alisertib (26.3% of the dose administered) were the major drug-related components in feces. In vitro, oxidative metabolism of alisertib was primarily mediated by CYP3A. The acyl glucuronidation of alisertib was primarily mediated by UGT1A1, 1A3, and 1A8 and was stable in 0.1M phosphate buffer and in plasma and urine. Further in vitro evaluation of alisertib and its metabolites M1 and M2 for CYP-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with co-administered drugs. Overall, renal elimination played an insignificant role in the disposition of alisertib, and metabolites resulting from phase I oxidative pathways contributed to >58% of the alisertib dose recovered in urine and feces over 192 hours post-dose.SIGNIFICANCE STATEMENT This study describes the primary clearance pathways of alisertib and illustrates the value of timely conduct of human ADME studies in providing guidance to the clinical pharmacology development program for oncology drugs, for which a careful understanding of sources of exposure variability is crucial to inform risk management for DDIs given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients. ER -