Mass balance, routes of excretion, and pharmacokinetics of investigational oral [14C]-alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors
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Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14C]-alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography–tandem mass spectrometry, and mass balance/recovery of [14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma Tmax, 1 h) for alisertib and TRA. Mean plasma t1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC0–inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC0–last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.
KeywordsAlisertib Mass balance Pharmacokinetics Aurora A kinase
The authors would like to thank all the study participants and their families. The authors thank Jaime Mertz of Millennium Pharmaceuticals, Inc. for her contributions to the oversight of operational aspects of this study and data analysis. The authors would like to acknowledge Dawn L. Lee of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., in compliance with Good Publication Practice 3 ethical guidelines (Battisti et al., Ann Intern Med 2015;163:461-4).
Compliance with ethical standards
Conflict of interests
X Zhou, S Pusalkar, S K. Chowdhury, Y Li, and K Venkatakrishnan are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
All participants provided written informed consent prior to any study-related procedures.
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