A Study to Determine the Effect of Food on the Pharmacokinetics of PCI-32765

Study Overview
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Brief Summary
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The purpose of this study is to compare the effect of food and two modified fasting regimens on the pharmacokinetics (study of what the body does to a drug) of PCI-32765 in healthy adult participants.

Detailed Description
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This is a randomized (individuals will be assigned by chance to study treatments), open-label (identity of assigned study drug will be known), 4-way crossover study to compare the effect of food and two fasting regimens on the pharmacokinetics of PCI-32765 in healthy adults. There will be approximately 52 (at least 25% women) participants (11 in each sequence in the 4-way crossover and 8 in an optional cohort). A screening phase will be followed by an open-label treatment phase consisting of 4 single-dose treatment periods of 420 mg PCI-32765 administered with or without food. Doses in successive open-label treatment periods will be separated by a washout period of 7 days. Participants will be confined to the study center from Day -1 of each treatment period (at least 10 hours before each study drug administration) until completion of the 72 hour pharmacokinetic blood sample collection on Day 4 of Period 4. Blood samples for pharmacokinetic analysis of PCI-32765 and metabolite PCI-45227 will be collected before dosing and over 72 hours after dosing in each treatment period. A follow-up visit approximately 10 days after the last dose will be made to measure lymphocyte count and to capture any additional adverse events. After completion of the 4-way crossover portion of the study, and in absence of significant safety observations at the 420 mg PCI-32765 dose, an additional separate cohort of 8 participants may be enrolled to participate in one treatment period and receive a dose of 840 mg in combination with a high-fat breakfast. Safety will be assessed throughout the study. The total study duration is a maximum of 85 days.

Official Title
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Open-Label, Randomized, 4-Way Crossover Study to Determine the Effect of Food on the Pharmacokinetics of PCI-32765

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Sequence 1: PCI-32765
* Drug: Sequence 2: PCI-32765
* Drug: Sequence 3: PCI-32765
* Drug: Sequence 4: PCI-32765
* Drug: Sequence 5: PCI-32765


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women must be postmenopausal or documented as surgically sterile Men must agree to use an adequate contraception method as deemed appropriate by the investigator during the study and for 3 months after receiving the last dose of study drug, and to not donate sperm during the study and for 3 months after receiving the last dose of study drug Body mass index between 18 and 30 kg/m2and body weight not less than 50 kg Blood pressure (after sitting for 5 minutes) between 90 and 140 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic Exclusion Criteria: History of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, neurologic or psychiatric disease, infection, history of immune disorders (eg, lupus, rheumatoid arthritis, psoriatic arthritis) or any other illness that the investigator considers should exclude the participant or that could interfere with the interpretation of the study results Clinically significant abnormal values for hematology, coagulation, PFA-100, clinical chemistry or urinalysis at screening Clinically significant abnormal physical examination, vital signs or 12 lead electrocardiogram (ECG) at screening Use of aspirin, non-steroidal anti-inflammatory agents, clopidogrel, Vitamin E supplements, fish oil, or flax seed within 1 week before PFA-100 assay test at screening Use of any prescription or nonprescription medication (including vitamins and herbal supplements), except for acetaminophen, and hormonal replacement therapy, within 14 days before the first dose of the study drug is scheduled Use of herbal supplements (such as St. John's Wort) within 30 days of the first dose administration Has a history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV) criteria within 2 years before screening or positive test result(s) for alcohol and/or drugs of abuse (such as barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) at screening and Day -1 of each treatment period History of clinically significant allergies, especially known hypersensitivity or intolerance to sulfonamide or beta-lactam antibiotics Known allergy to the study drug or any of the excipients of the formulation Known allergy to heparin or history of heparin induced thrombocytopenia Donated blood or blood products or had substantial loss of blood within 3 months before the first administration of study drug or intention to donate blood or blood products during the study Received an experimental drug or used an experimental medical device within 1 month or within a period less than 10 times the drug's half life, whichever is longer, before the first dose of the study drug is scheduled Unable to swallow solid, oral dosage forms whole with the aid of water (participants may not chew, divide, dissolve, or crush the study drug) Positive test for human immunodeficiency virus (HIV) 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies History of smoking or use of nicotine-containing substances within the previous 2 months, as determined by medical history or participant's verbal report and confirmed by cotinine test Preplanned surgery or procedures that would interfere with the conduct of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: PCI-32765<br>420 mg capsules administered by mouth with 240 mL noncarbonated water 30 minutes after completing a high-fat breakfast | Drug: Sequence 1: PCI-32765<br>* Period 1 = Treatment D, Period 2 = Treatment C, Period 3 = Treatment A, Period 4 = Treatment B<br>Drug: Sequence 2: PCI-32765<br>* Period 1 = Treatment A, Period 2 = Treatment D, Period 3 = Treatment B, Period 4 = Treatment C<br>Drug: Sequence 3: PCI-32765<br>* Period 1 = Treatment B, Period 2 = Treatment A, Period 3 = Treatment C, Period 4 = Treatment D<br>Drug: Sequence 4: PCI-32765<br>* Period 1 = Treatment C, Period 2 = Treatment B, Period 3 = Treatment D, Period 4 = Treatment A<br>|
| Experimental: Treatment B: PCI-32765<br>420 mg capsules administered by mouth with 240 mL noncarbonated water after fasting for at least 10 hours and 30 minutes before starting a high-fat breakfast | Drug: Sequence 1: PCI-32765<br>* Period 1 = Treatment D, Period 2 = Treatment C, Period 3 = Treatment A, Period 4 = Treatment B<br>Drug: Sequence 2: PCI-32765<br>* Period 1 = Treatment A, Period 2 = Treatment D, Period 3 = Treatment B, Period 4 = Treatment C<br>Drug: Sequence 3: PCI-32765<br>* Period 1 = Treatment B, Period 2 = Treatment A, Period 3 = Treatment C, Period 4 = Treatment D<br>Drug: Sequence 4: PCI-32765<br>* Period 1 = Treatment C, Period 2 = Treatment B, Period 3 = Treatment D, Period 4 = Treatment A<br>|
| Experimental: Treatment C: PCI-32765<br>420 mg capsules administered by mouth with 240 mL noncarbonated water 2 hours after completing a high-fat breakfast | Drug: Sequence 1: PCI-32765<br>* Period 1 = Treatment D, Period 2 = Treatment C, Period 3 = Treatment A, Period 4 = Treatment B<br>Drug: Sequence 2: PCI-32765<br>* Period 1 = Treatment A, Period 2 = Treatment D, Period 3 = Treatment B, Period 4 = Treatment C<br>Drug: Sequence 3: PCI-32765<br>* Period 1 = Treatment B, Period 2 = Treatment A, Period 3 = Treatment C, Period 4 = Treatment D<br>Drug: Sequence 4: PCI-32765<br>* Period 1 = Treatment C, Period 2 = Treatment B, Period 3 = Treatment D, Period 4 = Treatment A<br>|
| Experimental: Treatment D: PCI-32765<br>420 mg capsules administered with 240 mL noncarbonated water after fasting at least 10 hours | Drug: Sequence 1: PCI-32765<br>* Period 1 = Treatment D, Period 2 = Treatment C, Period 3 = Treatment A, Period 4 = Treatment B<br>Drug: Sequence 2: PCI-32765<br>* Period 1 = Treatment A, Period 2 = Treatment D, Period 3 = Treatment B, Period 4 = Treatment C<br>Drug: Sequence 3: PCI-32765<br>* Period 1 = Treatment B, Period 2 = Treatment A, Period 3 = Treatment C, Period 4 = Treatment D<br>Drug: Sequence 4: PCI-32765<br>* Period 1 = Treatment C, Period 2 = Treatment B, Period 3 = Treatment D, Period 4 = Treatment A<br>|
| Experimental: Treatment E: PCI-32765<br>840 mg capsules administered with 240mL noncarbonated water 30 minutes after completing a high-fat breakfast | Drug: Sequence 5: PCI-32765<br>* After completion of the 4-way crossover, an additional separate cohort of 8 subjects were enrolled. These subjects participated in 1 treatment period to document safety and PK<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from time 0 to time the last quantifiable concentrations of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Area under the plasma concentration-time curve from time 0 to infinite time of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Maximum plasma concentration of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach the maximum plasma concentration of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Percentage of area under the plasma concentration-time curve from time 0 to infinite time obtained by extrapolation of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Elimination half-life of PCI-32765 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Relative bioavailability of PCI-32765 | Relative bioavailability is defined as the ratio of the area under the concentration curve to infinity between the test treatment and the reference treatment. | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Maximum plasma concentration of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Time to reach the maximum plasma concentration of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Area under the plasma concentration-time curve from time 0 to time the last quantifiable concentrations of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Area under the plasma concentration-time curve from time 0 to infinite time of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Percentage of area under the plasma concentration-time curve from time 0 to infinite time obtained by extrapolation of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Elimination half-life of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Relative bioavailability of metabolite PCI-45227 |  | Predose; postdose at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours | 
| Number of participants with adverse events |  | Up to 30 days following the last dose of study drug | 
| Number of participants with adverse events of special interest (major hemorrhage and intracranial hemorrhage) |  | Up to 30 days following the last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, PCI-32765, PCI-45227, Pharmacokinetics