Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion

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

PurposeTo assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability.MethodsThree 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.ResultsAdministration 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.ConclusionsIbrutinib 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

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion

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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-015-2708-9) contains supplementary material, which is available to authorized users