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

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02568176
• Other study ID #: CR108043
• Secondary ID: ESKETINTRD101020
• Status: Completed
• Phase: Phase 1
• First received: October 2, 2015
• Last updated: February 16, 2017
• Start date: October 2015
• Est. completion date: February 2016

Study information

• Verified date: February 2017
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 71
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Midazolam
Single oral dose of midazolam 6 mg Day 1 and Day 17.
• Esketamine
Intranasal esketamine will be self-administered 5 times during 15 days.
• Bupropion
Single oral dose of bupropion 150 mg on Day 1 and 19.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Renal clearance	Renal clearance calculated as Ae/AUC (infinity).	up to Day 19 for Cohort 2
Primary	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
Primary	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	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2