@article{15bd1d73b4e745deb760838c8dd7a28f,
title = "Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Dysfunction",
abstract = "This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN < total bilirubin ≤ 3 × ULN, with any ALT) or severe hepatic impairment (total bilirubin > 3 × ULN, with any ALT), received a single 50-mg oral dose of alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess alisertib plasma protein binding. Patients could continue to receive alisertib for 7 days in 21-day cycles (50, 30, or 10 mg twice daily for normal hepatic function, moderate hepatic impairment, and severe hepatic impairment, respectively). Alisertib was approximately 99% protein bound in all hepatic function groups. Alisertib exposure was similar in moderate and severe hepatic impairment groups, but higher than the normal hepatic function group. The geometric least-squares mean ratios (90% confidence intervals) for unbound alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations.",
keywords = "Aurora A kinase, alisertib, hepatic impairment, pharmacokinetics",
author = "Xiaofei Zhou and Lockhart, {A. Craig} and Siqing Fu and John Nemunaitis and John Sarantopoulos and Andreas Muehler and Lakshmi Rangachari and Michael Bargfrede and Karthik Venkatakrishnan",
note = "Funding Information: The authors thank all patients included in this study and their families, as well as all physicians, nurses, study coordinators, and study center staff participating in the study. The authors acknowledge the following cancer center grant: the Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center San Antonio; San Antonio, Texas, Cancer Center Support Grant P30CA054174. The authors thank Washington University St. Louis IRB (St. Louis, Missouri), Office for Protection of Research Studies (Chicago, Illinois), and University of Michigan/IRBMED (Ann Arbor, Michigan) for their review of the study. The authors also acknowledge Samantha Abel of Valley Writing Solutions Ltd (Canterbury, UK), who provided medical editing assistance during the development of this article, which was funded by Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Funding Information: This study was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Funding Information: This study was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The authors thank all patients included in this study and their families, as well as all physicians, nurses, study coordinators, and study center staff participating in the study. The authors acknowledge the following cancer center grant: the Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center San Antonio; San Antonio, Texas, Cancer Center Support Grant P30CA054174. The authors thank Washington University St. Louis IRB (St. Louis, Missouri), Office for Protection of Research Studies (Chicago, Illinois), and University of Michigan/IRBMED (Ann Arbor, Michigan) for their review of the study. The authors also acknowledge Samantha Abel of Valley Writing Solutions Ltd (Canterbury, UK), who provided medical editing assistance during the development of this article, which was funded by Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Xiaofei Zhou, Andreas Muehler, Lakshmi Rangachari, and Karthik Venkatakrishnan are employed by Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. This study was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Takeda makes patient-level, deidentified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data-Sharing Policy (see https://www.takedaclinicaltrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, which will review the scientific merit of the research and the requester's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data-sharing agreement are provided access to these data in a secure research environment. Publisher Copyright: {\textcopyright} 2019, The American College of Clinical Pharmacology",
year = "2019",
doi = "10.1002/jcph.1416",
language = "English (US)",
volume = "59",
pages = "1204--1215",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "9",
}