Abstract P1-10-14: Abemaciclib tablet formulation is bioequivalent to capsules
Authors: PK Turner, JC Chappell, A Aburub, WT Ng, W Zhang, J Royalty, P Kulanthaivel
Journal: Cancer Research (2018)

Abstract Introduction: Abemaciclib is being developed for the treatment of cancer, including advanced and metastatic breast cancer. Tablet formulations, which are smaller than the capsules used in the pivotal MONARCH 1, 2 and 3 breast cancer studies, have recently been developed. This study evaluated the bioequivalence of abemaciclib capsule and tablet formulations following single 150-mg doses, and the effect of food on the pharmacokinetics (PK) of abemaciclib following dosing with a 150-mg tablet. Methods: This was an open-label, randomized, 3-part study conducted in 127 healthy male (13%) and female (87%) subjects. Plasma concentrations of abemaciclib and its major metabolites were assessed up to 192 hours postdose using validated LC-MS/MS methods. Part A was a 2-period, crossover pilot study to compare abemaciclib capsules (3 x 50-mg) and tablets (1 x 150-mg) formulations in the fasted state. Results from Part A were used to ensure adequate PK sampling and estimate intra-individual variability to confirm the sample size required for Part B of the study. Part B was a 3-period, crossover, bioequivalence study of a 50-mg capsule (3 x 50-mg) compared to a 150-mg tablet (1 x 150-mg) and a 50mg tablet (3 x 50-mg) in the fasted state. Part C was a 2-period crossover food effect study to determine the effect of a high-fat, high-calorie meal on the PK of abemaciclib when administered as a single 150-mg tablet compared to the fasted state. Abemaciclib Cmax and AUC determined using noncompartmental methods were log-transformed and analyzed using a linear mixed-effects model. Geometric least squares (LS) mean for each treatment, the ratio of the geometric LS means, and their 90% CIs were calculated. Results: In Part A, the abemaciclib intra-subject variability for Cmax was 26.7%, requiring a sample size of 76 subjects for Part B to ensure approximately 90% probability that the 90% CIs of the geometric means would be contained within the 0.80 to 1.25 limits, assuming that the true ratio was 1.09. In Part B, both the 3 x 50-mg and 1 x 150-mg tablets were bioequivalent to the 3 x 50-mg capsules; the 90% CIs of the ratios of geometric LS means for Cmax and AUC were contained within the bioequivalence interval of 0.80 to 1.25. Ratio of geometric LS mean (90% CI) compared to 3x50 mg capsule 1x150 mg tablet3x50 mg tabletAUC(0-tlast)1.02 (0.979,1.06)1.03 (0.987,1.07)AUC(0-∞)1.02 (0.982,1.06)1.02 (0.986,1.06)Cmax1.00 (0.955,1.05)1.03 (0.986,1.08) In Part C, consumption of a high-fat, high-calorie meal before abemaciclib dosing resulted in an increase of 13% (90% CI 1.05,1.22) in AUC(0-∞) and 30% (90% CI 1.20,1.40) in Cmax, which was not considered clinically relevant given the magnitude of the effect relative to the inter-subject variability for Cmax (36.5%). Also, the magnitude of the change was within the therapeutic window for abemaciclib. There was no difference in median tmax in the fed state compared to the fasted state for abemaciclib. Single 150-mg doses of abemaciclib were generally well tolerated when administered with or without food. The majority of the AEs reported during the study were gastrointestinal and mild in severity. Conclusions: Abemaciclib 150-mg and 50-mg tablets are bioequivalent to the 50-mg capsule formulation, based on a single dose in the fasted state, and could be administered with or without food. Citation Format: Turner PK, Chappell JC, Aburub A, Ng WT, Zhang W, Royalty J, Kulanthaivel P. Abemaciclib tablet formulation is bioequivalent to capsules [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-14.