Abstract 4637: Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients
Authors: Jong Jan de , Sukbuntherng Juthamas , Skee Donna , Murphy Joe , O'Brien Susan , Byrd John C. , James Danelle , Hellemans Peter , Jiao Juhui James , Chauhan Vijay , Poggesi Italo , Mannaert Erik 
Published: May 2015

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy treated with chemoimmunotherapy. Such treatment results in high response rates but patients may eventually relapse and require alternate therapies. Ibrutinib (PCI-32765), a recently developed novel treatment, is unique in its mechanism as it inhibits Bruton's tyrosine kinase, a key kinase in the B-cell receptor signaling pathway. It's a Biopharmaceutics Classification Systems (BCS) class 2 compound and is metabolized rapidly by CYP3A. Three studies were conducted. The primary objectives were to assess the pharmacokinetics (PK) of ibrutinib under fed and fasted conditions and to assess the impact of food intake timing. Additionally, the safety and tolerability of ibrutinib were assessed. Study 1 was a randomized, open-label, single-center, single-dose, 4-way crossover study in 44 healthy subjects. Study 2 was a multicenter, randomized, repeated-dose crossover study in 16 patients with relapsed or refractory CLL. The ibrutinib dose was 420 mg in both. Study 3 was an open-label, single-center, sequential study to assess absolute bioavailability of ibrutinib 560 mg in 8 healthy subjects.

Ibrutinib was well tolerated in these studies. There were no serious adverse events (AEs) or discontinuations due to an AE. There were no clinically significant changes in laboratory safety parameters, electrocardiograms, or vital signs. Administration of ibrutinib to healthy subjects under fasting conditions resulted in approximately 60% of exposure compared to drug intake either 30 min before or 2 h after a high-fat meal. When ibrutinib was taken 30 min after a meal, drug exposure was comparable to the dosing conditions of either 30 min before or 2 h after the meal. Study 2 revealed that under fed conditions, the maximum concentration was 2.24 times greater and the area under the curve was 1.65 times greater compared to the fasted conditions, but similar to uncontrolled food intake conditions. A similar food effect was observed in study 3, in which a standard meal was consumed starting 30 min after dosing. When corrected for repeated dosing in patients, the PK parameters in healthy subjects and patients were comparable.

The observed food effect is most likely the result of a decreased (intestinal and hepatic) first-pass effect, rather than an effect on solubilization. Since ibrutinib is a highly permeable compound, residence time in the gut and liver cells could be reduced when mesenteric and portal vein blood flow is increased under fed conditions, making ibrutinib less available to CYP3A clearance. The effect on bioavailability may outweigh the higher clearance due to liver blood flow.

In conclusion, food causes no more than a doubling in ibrutinib systemic exposure. Considering the favorable safety profile, ibrutinib can be administered with or without food.

Citation Format: Jan de Jong, Juthamas Sukbuntherng, Donna Skee, Joe Murphy, Susan O'Brien, John C. Byrd, Danelle James, Peter Hellemans, Juhui James Jiao, Vijay Chauhan, Italo Poggesi, Erik Mannaert. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2014-4637