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.
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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
71
Single oral dose of midazolam 6 mg Day 1 and Day 17.
Intranasal esketamine will be self-administered 5 times during 15 days.
Single oral dose of bupropion 150 mg on Day 1 and 19.
Unnamed facility
Merksem, Belgium
Maximum Plasma Concentration (Cmax)
The Cmax is the maximum plasma concentration.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: up to Day 19 for Cohort 2
Renal clearance
Renal clearance calculated as Ae/AUC (infinity).
Time frame: 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.
Time frame: 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.
Time frame: up to Day 19 for Cohort 2
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.
Time frame: Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2