Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors

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 t max 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 C max 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.

Figures

Fig. 1

Study design. *Dose escalation to 50 mg twice daily was allowed at any point after cycle 1 based on tolerability and objective safety findings in the previous cycles (for example, no dose-limiting toxicity or grade 4 toxicity of any duration). Twenty-four patients were randomized (sequence A, n = 1 2; sequence B, n = 12). BID twice daily, D day, ECT enteric-coated tablet, PK pharmacokinetics

Fig. 2

Mean alisertib plasma concentration–time profiles following single-dose administration of alisertib ECT 50 mg in the fed (n = 14) or fasted state (n = 14) on a a linear scale and b a semi-logarithmic scale. ECT enteric-coated tablet

Fig. 3

Alisertib a AUCinf and bCmax in individual patients following single-dose administration of alisertib ECT 50 mg under fed or fasted conditions. *The terminal phase of the alisertib plasma concentration–time profile was not sufficiently defined in three patients. AUCinf area under the plasma concentration–time profile from time zero to infinity, Cmax maximum plasma concentration, ECT enteric-coated tablet