Clinical trial NCT02617810: A Study to Assess the Effect of Multiple-Dose Administration of JNJ-42847922 on Midazolam and Warfarin in Healthy Participants
Official title: An Open-Label Drug Interaction Study to Assess the Effect of Multiple-Dose Administration of JNJ-42847922 on the Single-Dose Pharmacokinetics of Midazolam and the Single Dose Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Healthy
JNJ-42847922
Midazolam
Warfarin
Pharmacokinetics
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-12-01
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate effect of multiple-dose administration of JNJ-42847922 on the single-dose pharmacokinetics of oral midazolam and single-dose pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin after oral administration of racemic warfarin.

Detailed description: This is an open-label (all people know the identity of the intervention), single-center, fixed-sequence, study of JNJ-42847922 in healthy participants. The study consists of 3 Phases: Screening Phase (28 Days), open-label treatment Phase (40 Days) and follow up visit (7 to 14 Days after last study procedure). The duration of participation in the study for each participant is approximately 82 Days. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Signed an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study
* Willing to adhere to the prohibitions and restrictions specified in protocol
* If a woman, must be not of child-bearing potential: postmenopausal \[greater than or equal to (\>=) 45 years of age with amenorrhea for at least 2 years, or any age with amenorrhea for at least 6 months and a serum stimulating hormone (FSH) greater than (\>) 40 International units per liter (IU/L), or surgically sterile (example, hysterectomy, oophorectomy, tubal ligation or tubal occlusion)
* If a woman, must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction for at least 3 months after the last dose of study drug
* If a man who is sexually active with a woman of childbearing potential and has not had a vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator (example, vasectomy, double-barrier, partner using effective contraception) and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
* Body mass index (BMI) between 18 and 30 kilogram (kg)/meter\^2 (m\^2), and body weight not less than 50 kg

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), syncope, hypotension, hypertension or vascular disorders, lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, hepatic or renal insufficiency, kidney or urinary tract disturbances, thyroid disease, neurologic disease, significant psychiatric disorder, epilepsy, or fits of unexplained black-outs, infection, 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, clinical chemistry, urinalysis, or thyroid stimulating hormone (TSH) at Screening or at Day -1 of the first treatment period as deemed appropriate by the Investigator. In addition, participants must have coagulation test results \[(prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT)\] within clinically acceptable limits at Screening as deemed appropriate by the Investigator
* Clinically significant abnormal physical examination, vital signs, or 12 lead electrocardiogram (ECG) at Screening or Day -1 of the first treatment period as deemed appropriate by the Investigator
* Participants who are homozygous or heterozygous for CYP2C9\*2 or CYP2C9\*3 alleles
* Use of any prescription or nonprescription medication (including vitamins and herbal supplements), except for acetaminophen, within 14 days before the first dose of the study drug is scheduled until completion of the study. In addition, participants will be excluded if they have used medications known to affect coagulation or modulate CYP2C9 or VKORC1 within 28 days of study admission

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Maximum Plasma Concentration (Cmax) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Maximum Plasma Concentration (Cmax) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Time of Last Measurable Plasma Concentration (Tlast) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Time of Last Measurable Plasma Concentration (Tlast) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Time of Last Measurable Plasma Concentration (Tlast) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Terminal Half-life (t[1/2]) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Terminal Half-life (t[1/2]) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Terminal Half-life (t[1/2]) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Total Apparent Clearance (CL/F) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Total Apparent Clearance (CL/F) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Total Apparent Clearance (CL/F) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Apparent Volume of Distribution (Vd/F) of Midazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Apparent Volume of Distribution (Vd/F) of 1-Hydroxymidazolam
timeFrame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B
measure: Apparent Volume of Distribution (Vd/F) of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Maximum Observed Effect (Emax) for Prothrombin Time (PT)
timeFrame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Maximum Observed Effect (Emax) for activated Partial Thromboplastin Time (aPTT)
timeFrame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Maximum Observed Effect (Emax) for International Normalized Ratio (INR)
timeFrame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of JNJ-42847922
timeFrame: 2 hours postdose on Day 1 to Day 6; 2 and 26 hours postdose on Day 7; 2 hours postdose on Day 9 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to 168 Hours (AUC[0-168]) Post Dose of Warfarin
timeFrame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B
measure: Area Under the Plasma Concentration-Time Curve From 0 to 168 Hours (AUC[0-168]) Post Dose of JNJ-42847922
timeFrame: 2 hours postdose on Day 1 to Day 6; 2 and 26 hours postdose on Day 7; 2 hours postdose on Day 9 during Treatment B
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: Day -1 of Treatment A dosing
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: 4 hours postdose on Day 1 during Treatment A
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: 8 hours postdose on Day 1 during Treatment A
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: Day -1 of Treatment B dosing
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: 4 hours postdose on Day 7 during Treatment B
measure: Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)
timeFrame: 8 hours postdose on Day 7 during Treatment B
Secondary outcomes:
measure: Number of Participants with Adverse Events (AEs) and Serious AEs
timeFrame: Screening up to follow-up visit (7 to 14 days after last study procedure)
Other outcomes:
Locations:
city: Overland Park
country: United States
state: Kansas
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: