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Research ArticleArticle

Biotransformation Pathways and Metabolite Profiles of Oral [14C]Alisertib (MLN8237), an Investigational Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Sandeepraj Pusalkar, Xiaofei Zhou, Yuexian Li, Lawrence Cohen, Jun Johnny Yang, Suresh K. Balani, Cindy Xia, Wen Chyi Shyu, Chuang Lu, Karthik Venkatakrishnan and Swapan K. Chowdhury
Drug Metabolism and Disposition March 2020, 48 (3) 217-229; DOI: https://doi.org/10.1124/dmd.119.087338
Sandeepraj Pusalkar
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Xiaofei Zhou
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Yuexian Li
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Lawrence Cohen
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Jun Johnny Yang
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Suresh K. Balani
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Cindy Xia
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Wen Chyi Shyu
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Chuang Lu
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Karthik Venkatakrishnan
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Swapan K. Chowdhury
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
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Abstract

Alisertib (MLN8237) is an investigational, orally available, selective aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematologic 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 postdose. Unchanged [14C]alisertib was the predominant drug-related component in plasma, followed by O-desmethyl alisertib (M2), and alisertib acyl glucuronide (M1), which were present at 47.8%, 34.6%, and 12.0% of total plasma radioactivity. In urine, of the 2.7% of the dose excreted, unchanged [14C]alisertib was a negligible component (trace), 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 uridine 5′-diphospho-glucuronosyltransferase 1A1, 1A3, and 1A8 and was stable in 0.1 M phosphate buffer and in plasma and urine. Further in vitro evaluation of alisertib and its metabolites M1 and M2 for cytochrome P450-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with coadministered drugs. Overall, renal elimination played an insignificant role in the disposition of alisertib, and metabolites resulting from phase 1 oxidative pathways contributed to >58% of the alisertib dose recovered in urine and feces over 192 hours postdose.

SIGNIFICANCE STATEMENT This study describes the primary clearance pathways of alisertib and illustrates the value of timely conduct of human absorption, distribution, metabolism, and excretion 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 drug-drug interactions given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients.

Footnotes

    • Received March 29, 2019.
    • Accepted December 9, 2019.
  • ↵1 Current affiliation: iHOPE Hill, LLC, Cambridge, Massachusetts.

  • ↵2 Current affiliation: Department of DMPK, Sanofi USA, Waltham, Massachusetts.

  • This study was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

  • Prior presentation: Sandeepraj Pusalkar, Xiaofei Zhou, Yuexian Li, et al. Absorption, metabolism, and excretion of alisertib (MLN8237), an Aurora A kinase inhibitor, in patients with advanced solid tumors or lymphomas. Poster presented at the 19th North American International Society for the Study of Xenobiotics (ISSX)/29th Japanese Society for the study of Xenobiotics (JSSX) Meeting; 19–October 23, 2014; San Francisco, CA, USA. Abstract P331.

  • https://doi.org/10.1124/dmd.119.087338.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (3)
Drug Metabolism and Disposition
Vol. 48, Issue 3
1 Mar 2020
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Research ArticleArticle

Alisertib Metabolic Profile in Patients with Advanced Solid Tumor

Sandeepraj Pusalkar, Xiaofei Zhou, Yuexian Li, Lawrence Cohen, Jun Johnny Yang, Suresh K. Balani, Cindy Xia, Wen Chyi Shyu, Chuang Lu, Karthik Venkatakrishnan and Swapan K. Chowdhury
Drug Metabolism and Disposition March 1, 2020, 48 (3) 217-229; DOI: https://doi.org/10.1124/dmd.119.087338

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Research ArticleArticle

Alisertib Metabolic Profile in Patients with Advanced Solid Tumor

Sandeepraj Pusalkar, Xiaofei Zhou, Yuexian Li, Lawrence Cohen, Jun Johnny Yang, Suresh K. Balani, Cindy Xia, Wen Chyi Shyu, Chuang Lu, Karthik Venkatakrishnan and Swapan K. Chowdhury
Drug Metabolism and Disposition March 1, 2020, 48 (3) 217-229; DOI: https://doi.org/10.1124/dmd.119.087338
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