Abstract CT152: Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject

Abstract

Abemaciclib is an oral, selective, and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for the treatment of patients with refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. The absolute bioavailability and effect of food on pharmacokinetics (PK) following a single 200-mg oral dose of abemaciclib in healthy subjects were evaluated in three studies (Table 1). Abemaciclib plasma concentrations were measured serially pre-dose through 192 hours post-dose. Non-compartmental analysis was used to calculate PK parameters, and a mixed-effects model was used for statistical inference. In Study 1 the absolute bioavailability of a 200-mg dose of abemaciclib was 45% (90% CI: 40%, 51%). In Study 2 the ratios of AUC0-? after a high-fat or standard meal compared to fasting showed no effect (90% CIs within 0.80, 1.25). However, Cmax increased by 24% and 25% following high-fat and standard meals, respectively, compared to fasting (upper 90% CIs >1.25). No differences were found in the AUC0-? and Cmax of abemaciclib following a high-fat meal compared to a standard meal (90% CI within 0.80, 1.25). The median tmax was delayed by 2 hours following a high-fat meal compared to fasting (p = 0006). However, there was no difference in median tmax between the standard meal and fasting (p = .7197). Abemaciclib terminal half-life was similar across fed and fasted conditions. The late-breaking Study-3 results will be presented. In conclusion, abemaciclib oral bioavailability is sufficient to achieve therapeutic exposure. Food with abemaciclib does not reduce or increase the inter-individual PK variability and does not have a clinically-relevant impact on the PK of abemaciclib. Therefore, abemaciclib may be administered without regard to food. Table 1Designs for three open-label clinical studies of abemaciclib as a single 200-mg oral dose administered to healthy subjectsStudy ParametersNCT02327143a (Study 1)I3Y-MC-JPBSNCT02059148a (Study 2)I3Y-MC-JPBGNCT02482935a (Study 3)I3Y-MC-JPBUCompleted subjects (N)82329Overall designs and formulationsAbsolute bioavailability, 4 x 50-mg (25% w/w) capsules and tracer IVbPilot food effect, randomized crossover 3 period, 6 sequence 4 x 50-mg (50% w/w) capsulesPivotal food effect, randomized crossover 2 period, 2 sequence 2 x 100-mg (25% w/w) capsulesMeal conditionFastedFastedStandard mealHigh-fat, high-calorie mealFastedHigh-fat, high-calorie meal Citation Format: Kellie Turner, Jill Chappell, Palaniappan Kulanthaivel, Wee Teck Ng, Jane Royalty. Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT152.

Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer

“…The absolute bioavailability of abemaciclib following a 200-mg oral dose in healthy individuals was found to be 45% based on an abstract from the 2016 American Association for Cancer Research Meeting. 3,7 In this study, administering abemaciclib with food did not appear to significantly affect the bioavailability; however, the C max was increased and the t max delayed 2 hours with the administration of meals. Based on the results of this study, it was determined that food does not have a clinically relevant impact on the pharmacokinetics of abemaciclib.…”

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

“…The tissue composition–based model (method 2) implemented in Simcyp as proposed by Rodgers et al was selected to predict the volume of distribution of abemaciclib at steady state. The tissue‐to‐plasma partition coefficient scalar was adjusted to 2.5 to match the observed Vd ss , calculated by noncompartmental analysis from intravenous (IV) data in the ABA study . The Vd ss of the 3 active metabolites was estimated manually, while clearance was kept fixed (see elimination section), based on the assumption that volume is the primary factor driving the metabolites’ peak pasma concentration (C max ).…”

“…Abemaciclib is extensively distributed to tissues, with a systemic volume of distribution at steady state (Vd ss ) estimated to be 724 L in the absolute bioavailability study. The mean half‐life and systemic clearance (CL) of abemaciclib are 29.3 hours and 24 L/h, respectively . Following oral administration of a 200‐mg dose, the oral bioavailability of abemaciclib is 45% …”

“…The mean half‐life and systemic clearance (CL) of abemaciclib are 29.3 hours and 24 L/h, respectively . Following oral administration of a 200‐mg dose, the oral bioavailability of abemaciclib is 45% …”

Abemaciclib as an original inhibitor of cyclin-dependent kinase for the treatment of luminal HER2-negative disseminated breast cancer

“…Прием абемациклиба с пищей, богатой жирами, или натощак не оказывал клинически значимого влияния на общую экспозицию препарата. В этой связи абемациклиб можно принимать независимо от еды [61].…”