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

NCT02568176 | Completed Phase 1

• 3 other identifiers: CR108043ESKETINTRD10102015-002654-13
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Healthy; Pharmacokinetics; Esketamine; JNJ-54135419; Midazolam; Bupropion

Outcome Measures

Primary Outcomes (14)

• Maximum Plasma Concentration (Cmax)

  The Cmax is the maximum plasma concentration.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Time to reach maximum concentration (tmax)

  Time to reach the maximum observed plasma concentration.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])

  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.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-last])

  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.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Terminal Half-Life(t[1/2])

  Terminal half-life (t\[(1/2\]) is defined as 0.693/Lambda(z).

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Area Under the Plasma Concentration-Time Curve From Time Zero to 12 hours (AUC [0-12])

  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.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Cmax metabolite to parent ratio (MPR Cmax)

  Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• AUC(last) metabolite to parent ratio (MPR AUC[last])

  AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• AUC (infinity) metabolite to parent ratio (MPR AUC [infinity])

  AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Amount of Drug excreted in Urine (Ae)

  Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.

  up to Day 17 for Cohort 1; up to Day 19 for Cohort 2

• Percentage of Drug dose excreted into urine

  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.

  up to Day 19 for Cohort 2

• Renal clearance

  Renal clearance calculated as Ae/AUC (infinity).

  up to Day 19 for Cohort 2

• Formation Clearance

  Formation clearance of drug, calculated as Ae of hydroxybupropion/AUC(infinity) of bupropion, and corrected for molecular weight if necessary.

  up to Day 19 for Cohort 2

• Ae metabolite to parent ratio (MPR Ae)

  Ae metabolite to parent ratio, and corrected for molecular weight if necessary.

  up to Day 19 for Cohort 2

Secondary Outcomes (1)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2

Study Arms (2)

Cohort 1

EXPERIMENTAL

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; Drug: Esketamine

Cohort 2

EXPERIMENTAL

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; Drug: Bupropion

Interventions

Midazolam DRUG

Single oral dose of midazolam 6 mg Day 1 and Day 17.

Cohort 1

Esketamine DRUG

Intranasal esketamine will be self-administered 5 times during 15 days.

Also known as: JNJ-54135419

Cohort 1; Cohort 2

Bupropion DRUG

Single oral dose of bupropion 150 mg on Day 1 and 19.

Cohort 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (1)

Unknown Facility

Merksem, Belgium

Location

Related Publications (1)

• Perez-Ruixo C, Rossenu S, Zannikos P, Nandy P, Singh J, Drevets WC, Perez-Ruixo JJ. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clin Pharmacokinet. 2021 Apr;60(4):501-516. doi: 10.1007/s40262-020-00953-4. Epub 2020 Oct 31.

  PMID: 33128208 DERIVED

MeSH Terms

Interventions

Midazolam; Esketamine; Bupropion

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Propiophenones; Ketones; Organic Chemicals

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2015
• First Posted: October 5, 2015
• Study Start: October 1, 2015
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: February 3, 2025

Record last verified: 2025-01

Locations

BE (1)