We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pharmacokinetic Study of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Participants

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02568176
Recruitment Status : Completed
First Posted : October 5, 2015
Last Update Posted : February 17, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
The primary purpose of this study is to evaluate the induction potential of repeated administration of intranasal esketamine on cytochrome P450 (CYP) 3A4 and CYP2B6 activity in healthy participants using orally administered midazolam and bupropion as probes, respectively and to evaluate the pharmacokinetics of esketamine after a single dose and repeated administration.

Condition or disease Intervention/treatment Phase
Healthy Drug: Midazolam Drug: Esketamine Drug: Bupropion Phase 1

Detailed Description:
This is a parallel group, single-center, repeat-dose, fixed-sequence, open-label (all people know the identity of the intervention), study. The effects of repeated administration of intranasal esketamine on the pharmacokinetics of midazolam and bupropion will be evaluated in Cohort 1 and Cohort 2, respectively. Participants in Cohort 1 will receive a single oral dose of midazolam in the morning of Day 1 and Day 17. Participants in Cohort 2 will receive a single oral dose of bupropion in the morning of Day 1 and Day 19. In Cohort 1 and 2 participants will self-administer 5 doses of intranasal esketamine over a 15-day period. The duration of study, from the Screening Phase through Follow-up, is up to 51 days and 54 days for Cohort 1 and Cohort 2, respectively. Blood samples for participants in Cohort 1 will be collected for up to 24 hours after dosing on Days 1 and 17 (midazolam) and for up to 24 hours on Days 2 and 16 (esketamine); For participants in Cohort 2, blood and urine samples for assessment of bupropion pharmacokinetics will be collected for up to 72 hours after dosing on Day 1 and Day 19. Participants' safety will be monitored throughout the study.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Study to Evaluate the Pharmacokinetics of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Subjects
Study Start Date : October 2015
Primary Completion Date : February 2016
Study Completion Date : February 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Cohort 1
Participants will receive single oral dose of midazolam 6 milligram (mg) on Day 1 and 17. Participants will self-administer esketamine intranasally thrice per day on morning of Day 2, 5, 9, 12 and 16 (84 mg).
Drug: Midazolam
Single oral dose of midazolam 6 mg Day 1 and Day 17.
Drug: Esketamine
Intranasal esketamine will be self-administered 5 times during 15 days.
Other Name: JNJ-54135419
Experimental: Cohort 2
Participants will receive single oral dose of bupropion 150 mg on Day 1 and 19. Participants will self-administer esketamine intranasally thrice per day on morning of Day 4, 7, 11, 14 and 18 (84 mg).
Drug: Esketamine
Intranasal esketamine will be self-administered 5 times during 15 days.
Other Name: JNJ-54135419
Drug: Bupropion
Single oral dose of bupropion 150 mg on Day 1 and 19.


Outcome Measures

Primary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    The Cmax is the maximum plasma concentration.

  2. Time to reach maximum concentration (tmax) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    Time to reach the maximum observed plasma concentration.

  3. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    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; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  4. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-last]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable 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; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  5. Terminal Half-Life(t[1/2]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    Terminal half-life (t[(1/2]) is defined as 0.693/Lambda(z).

  6. Area Under the Plasma Concentration-Time Curve From Time Zero to 12 hours (AUC [0-12]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    The AUC (0-12) is the area under the plasma concentration-time curve from time zero to 12 hours, 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; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  7. Cmax metabolite to parent ratio (MPR Cmax) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.

  8. AUC(last) metabolite to parent ratio (MPR AUC[last]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.

  9. AUC (infinity) metabolite to parent ratio (MPR AUC [infinity]) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.

  10. Amount of Drug excreted in Urine (Ae) [ Time Frame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2 ]
    Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.

  11. Percentage of Drug dose excreted into urine [ Time Frame: up to Day 19 for Cohort 2 ]
    Total amount excreted into the urine, expressed as a percentage of the administered dose, calculated as (Ae/dose)*100, and corrected for molecular weight if necessary.

  12. Renal clearance [ Time Frame: up to Day 19 for Cohort 2 ]
    Renal clearance calculated as Ae/AUC (infinity).

  13. Formation Clearance [ Time Frame: up to Day 19 for Cohort 2 ]
    Formation clearance of drug, calculated as Ae of hydroxybupropion/AUC(infinity) of bupropion, and corrected for molecular weight if necessary.

  14. Ae metabolite to parent ratio (MPR Ae) [ Time Frame: up to Day 19 for Cohort 2 ]
    Ae metabolite to parent ratio, and corrected for molecular weight if necessary.


Secondary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2 ]
    An AE was 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. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.


Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Be a man or woman of non-Asian origin 18 to 55 years of age, inclusive
  • 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
  • A woman of child-bearing potential, must have a negative serum β-human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine pregnancy test on Day -1 of the treatment period. Women using contraceptives must agree to use an additional birth control method during the study and for 1 month after receiving the last dose of study drug
  • 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 (eg, 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
  • Comfortable with self-administration of intranasal medication and able to follow instructions provided

Exclusion Criteria:

  • Clinically significant abnormal values for hematology, clinical chemistry (particularly potassium or magnesium levels below the normal laboratory range), or urinalysis at Screening or at admission to the study center (Day -1) as deemed appropriate by the investigator
  • Clinically significant abnormal physical examination, vital signs, or 12 lead electrocardiogram (ECG) at Screening or at admission to the study center (Day -1) as deemed appropriate by the investigator
  • Use of any prescription or non-prescription medication (including vitamins and herbal supplements), except for paracetamol, contraceptives, and hormonal replacement therapy, within 14 days before the first dose of the study drug is scheduled until completion of the study
  • Has used nasal tobacco powder ("snuff") regularly within the past year.
  • Has a nasal piercing
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02568176


Locations
Belgium
Merksem, Belgium
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
More Information

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02568176     History of Changes
Other Study ID Numbers: CR108043
ESKETINTRD1010 ( Other Identifier: Janssen Research & Development, LLC )
2015-002654-13 ( EudraCT Number )
First Posted: October 5, 2015    Key Record Dates
Last Update Posted: February 17, 2017
Last Verified: February 2017

Keywords provided by Janssen Research & Development, LLC:
Healthy
Pharmacokinetics
Esketamine
JNJ-54135419
Midazolam
Bupropion

Additional relevant MeSH terms:
Midazolam
Bupropion
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Agents
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors