The main purpose of this study is to evaluate the effects of repeat dosing of ibrutinib on the single-dose pharmacokinetics (PK) of oral contraceptives (OC - ethinylestradiol \[EE\] and levonorgestrel \[LN\]), the cytochrome P450 (CYP)2B6 probe bupropion and the CYP3A4 probe midazolam; and to evaluate the effects of single-dose ibrutinib on the single-dose PK of the CYP3A4 probe midazolam in female participants with B cell malignancy.
This is a multicenter study of ibrutinib (first-in-class, potent, covalently-binding inhibitor of Bruton's tyrosine kinase \[BTK\]) in female participants with B cell malignancy. The study consists of 3 phases: Screening Phase (up to 28 days), 7-day Pretreatment Phase (Days 1 to 7), Treatment Phase including PK assessment period (Days 8 to 26) and a Follow-up Phase (Day 27 to end of Cycle 6). The study procedures includes electrocardiogram (ECG), vital signs, blood samples withdrawal to evaluate PK and safety. The Antitumor activity will be assessed by means of computed tomography (CT) imaging and positron emission tomography (PET) scans. No formal statistical hypothesis will be tested. This is an estimation study designed to determine if an increase or decrease in exposure to OC or probe drugs occurs in the presence of ibrutinib.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
25
Ibrutinib capsule (at dose of 420 or 560 mg) will be taken orally QD.
Single dose of oral contraceptives (OC) (1 tablet containing 30 mcg EE and 150 mcg LN) will be taken orally on Study Days 1 and 22.
Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24.
Midazolam 2 mg (1 milliliter \[mL\]) oral solution will be taken on Study Days 3 and 24 (as a part of CYP cocktail) and on Study Day 8 (alone).
Pratia MCM Krakow
Krakow, Poland
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
Wroclaw, Poland
Hosp. Univ. Fund. Jimenez Diaz
Madrid, Spain
Clinica Univ. de Navarra
Pamplona, Spain
Maximum Observed Plasma Concentration (Cmax) of Ethinylestradiol (EE) and Levonorgestrel (LN) When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The Cmax is the maximum observed plasma concentration.
Time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours (h) post-dose
Maximum Observed Plasma Concentration (Cmax) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The Cmax is the maximum observed plasma concentration.
Time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
The Cmax is the maximum observed plasma concentration.
Time frame: Day 3: predose, 15 minutes (min), and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
Maximum Observed Plasma Concentration (Cmax) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
The Cmax is the maximum observed plasma concentration.
Time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
Time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
Time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
Time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
Time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of EE and LN When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Time frame: Days 1 and 22: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Bupropion and 4-Hydroxybupropion When Co-administered With Repeat Doses of Ibrutinib Compared to Administration Alone
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Time frame: Days 3 and 24: predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 34, 48, 58 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Repeat Doses of Ibrutinib
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 24: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 24 h post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Midazolam and 1-Hydroxymidazolam When Co-Administered With Single Dose of Ibrutinib
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Time frame: Day 3: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10,12, and 24 h post-dose; Day 8: predose, 15 min, and 0.5,1,2,3,4,5,6,8,10, and 12 h post-dose
Plasma Concentration of Ibrutinib and its Metabolite PCI-45227
Plasma concentrations of Ibrutinib and its Metabolite PCI-45227 will be measured.
Time frame: Predose, 1, 2, 4, and 6 h post-dose on Days 8, 22, and 24
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time frame: Screening up to end of the 6 month treatment or 30 days after the last dose of study drug for Participants discontinuing treatment before 6 months
Number of Participants With Laboratory Abnormalities as a Measure of Safety and Tolerability
Blood samples for serum chemistry and hematology will be collected at predefined time points for clinical laboratory testing.
Time frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability
Triplicate ECG will be performed at screening and a single time point ECG will be performed at end of treatment visit.
Time frame: Screening and End of Treatment (approximately 7 months)
Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability
Vital signs includes Temperature, Heart Rate, Respiratory Rate and Blood Pressure.
Time frame: Screening, Days 8 and 36, and End of Treatment (approximately 7 months)
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