Clinical trial NCT02568176: Pharmacokinetic Study of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Participants
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Healthy
Pharmacokinetics
Esketamine
JNJ-54135419
Midazolam
Bupropion
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-10-05
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax)
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Time to reach maximum concentration (tmax)
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-last])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Terminal Half-Life(t[1/2])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 12 hours (AUC [0-12])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Cmax metabolite to parent ratio (MPR Cmax)
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: AUC(last) metabolite to parent ratio (MPR AUC[last])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: AUC (infinity) metabolite to parent ratio (MPR AUC [infinity])
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Amount of Drug excreted in Urine (Ae)
timeFrame: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
measure: Percentage of Drug dose excreted into urine
timeFrame: up to Day 19 for Cohort 2
measure: Renal clearance
timeFrame: up to Day 19 for Cohort 2
measure: Formation Clearance
timeFrame: up to Day 19 for Cohort 2
measure: Ae metabolite to parent ratio (MPR Ae)
timeFrame: up to Day 19 for Cohort 2
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2
Other outcomes:
Locations:
city: Merksem
country: Belgium
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.