Abstract
Objective: This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Methods: Following overnight fasting for 10 h, a single 50 mg enteric-coated tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration. Results: Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median tmax was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUCinf (fed- vs. fasted-state dosing) was 0.94 [90 % confidence interval (CI) 0.68–1.32]. The geometric mean Cmax under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %). Conclusions: Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. ClinicalTrials.gov Identifier: NCT00962091.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 45-52 |
| Number of pages | 8 |
| Journal | Drugs in R and D |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - Mar 1 2016 |
Funding
The authors would like to thank the patients who participated in these studies, their supportive families, and the caring staff at all investigational sites. They would also like to acknowledge Catherine Crookes and Nadia Korfali of FireKite (an Ashfield company, part of UDG Healthcare plc) for writing assistance in the development of this manuscript, which was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. This work was supported by the National Institutes of Health (NIH) Clinical and Translational Science Award UL1 RR024148, the Cancer Center Support Grant (CCSG) P30CA054174 to the Cancer Therapy and Research Center, University of Texas Health Science Center San Antonio, and the NIH CCSG award CA016672 to the MD Anderson Cancer Center. G. S. Falchook and X. Zhou contributed equally to this work. This research was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Gerald S. Falchook has received research funding and travel reimbursements from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Foundation Medicine, Pfizer, Guardant and Sequenom, as well as consultant fees from Sequenom, and has ownership interest in RScueRX, Inc. Lee S. Rosen has received research support from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Xiaofei Zhou, Karthik Venkatakrishnan, JungAh Jung, and Catherine Milch are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Devalingam Mahalingam, Jonathan W. Goldman, and John Sarantopoulos have no conflicts of interest to disclose.
ASJC Scopus subject areas
- Pharmacology