The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia

Abstract

Purpose: To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability.

Methods: Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants.

Results: Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied.

Conclusions: Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib.

Trial registration: ClinicalTrials.gov NCT01105247 NCT01820936 NCT01866033.

Figures

Fig. 1

Treatment sequence. a Study 1: healthy participants receiving single-dose oral ibrutinib, b study 2: patients with previously treated chronic lymphocytic leukemia receiving repeat-dose oral ibrutinib, c study 3: healthy participants receiving single-dose oral ibrutinib. PK pharmacokinetics. Treatment A = Ibrutinib orally administered after fasting for ≥10 and 4 h before the next food-intake. Treatment B = Ibrutinib orally administered after fasting for ≥10 h and 30 min before a meal. Treatment C = Ibrutinib orally administered 2 h after a meal. Treatment D = Ibrutinib orally administered 30 min after completing a meal. Treatment X = Ibrutinib orally administered at least 30 min before or at least 2 h after a meal. aHealthy participants receiving single-dose study drug. bPatients with previously treated chronic lymphocytic leukemia receiving repeat-dose study drug

Fig. 2

a Log-linear time versus concentration curve in plasma following 420 and 560 mg oral ibrutinib administration with various meal and meal-time adjustments in healthy participants and patients with chronic lymphocytic leukemia. b Cross-study comparisons of Cmax and AUC in fed and fasting conditions. AUC area under the plasma concentration–time curve, Cmax maximum observed plasma concentration. Treatment A = Ibrutinib orally administered after fasting for ≥10 and 4 h before the next food-intake. Treatment B = Ibrutinib orally administered after fasting for ≥10 h and 30 min before starting a meal. Treatment C = Ibrutinib orally administered 2 h after a meal. Treatment D = Ibrutinib orally administered 30 min after completing a meal. Treatment X = Ibrutinib orally administered at least 30 min before or at least 2 h after a meal. aStudy 2 treatments A and D dose obtained at steady state, all others after single-dose. bDose normalized to a 420 mg dose

Fig. 3

Correlation between clearance rate of ibrutinib and food effect on AUC