A Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Participants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of esketamine administered by the intranasal (administered through the nose) and oral routes and to evaluate the effects of clarithromycin on the pharmacokinetics of intranasally administered esketamine.

Detailed Description
-----------------
This is a single-center, 4-period, fixed-sequence, open-label study. The study consists of Screening Period (Days -21 to -2), Open-label Treatment Period 1, 2, 3, 4 and End of Study (9 to 13 days after final dose or at Early Withdrawal). The total duration of study will be up to 98 days. For all 4 periods, the participants will be admitted into the study center on Day -1 of each treatment period and receive a 28 milligram (mg) (intravenous) or 84 mg (oral and intranasal) esketamine dose regimen on Day 1 of each period in a fixed sequence. Participants will also receive 500 mg of clarithromycin in period 4. Blood samples will be collected to evaluate the pharmacokinetic parameters. Participants' safety will be monitored throughout the study.

Official Title
-----------------
An Open-Label Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Subjects

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Esketamine
* Drug: Clarithromycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For women of childbearing potential, must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening; and a negative urine pregnancy test on Day -1 of Period 1 If a man, must agree to use an adequate contraception method as deemed appropriate by the investigator (example, 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 Participants with body mass index (BMI) between 18 and 30 kilogram per square meter (kg/m^2) (inclusive), and body weight not less than 50 kg Participants with blood pressure (after the participant is supine for 5 minutes) between 90 and 140 millimeter of mercury (mmHg) systolic, inclusive, and no higher than 90 mmHg diastolic Participants should be comfortable with self-administration of intranasal medication and able to follow instructions provided Exclusion Criteria: Participants diagnosed with a psychiatric disorder including but not limited to psychotic, bipolar, major depressive, or anxiety disorder Participants with clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, neurologic disease, infection, hypertension or vascular disorders, kidney or urinary tract disturbances, sleep apnea, myasthenia gravis, or any other illness that the investigator considers should exclude the participant or that could interfere with the interpretation of the study results Participants with 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 of Period 1) as deemed appropriate by the investigator Participants with clinically significant abnormal physical examination and vital signs at screening or at admission to the study center (Day -1 of Period 1) as deemed appropriate by the investigator Participants with history of drug or alcohol abuse disorder within the past 1 year, or a reason to believe a participant has such a history

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esketamine Regimen<br>All participants will first receive 28 milligram (mg) of esketamine as a single, 40-minute, intravenous infusion on Day 1 of Period 1, followed by 84 mg of esketamine solution as a single, oral dose on Day 1 of Period 2, followed by 84 mg of intranasal esketamine on Day 1 of Period 3 and then 500 mg of clarithromycin twice daily on Days -3, -2, -1, 1, and 2 of Period 4 and 84 mg of intranasal esketamine on Day 1 of Period 4. Each period will be separated by a washout period of up to 21 days in between. | Drug: Esketamine<br>* 28 mg of esketamine as a single, 40-minute, intravenous infusion on Day 1 of Period 1, 84 mg of esketamine solution as a single, oral dose on Day 1 of Period 2, 84 mg of intranasal esketamine on Day 1 of Period 3 and on Day 1 of Period 4.<br>Drug: Clarithromycin<br>* 500 mg of clarithromycin twice daily on Days -3, -2, -1, 1, and 2 of Period 4.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Esketamine | The Cmax is the maximum plasma concentration. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Esketamine | The Tmax is time to reach the maximum plasma concentration. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC12h) of Esketamine | The (AUC12h) is the area under the plasma concentration-time curve from time 0 to 12 hours Post-dose. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hour (hr) post-dose on Day 1 in all periods | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Esketamine | The (AUC [0-last]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of Esketamine | 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(0-last) and C(0-last)/lambda(z), wherein AUC(0-last) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentrations; C(0-last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Percentage of Area Under the Plasma Concentration-time Curve Obtained by Extrapolation (%AUC [infinity,ex]) of Esketamine | Percentage of area under the plasma concentration-time curve obtained by extrapolation (%AUC[inf,ex]) is calculated by dividing the difference of AUC(0-infinity) and AUC(0-last) by AUC(0-infinity) and then multiplying by 100 (AUC[0-infinity] - AUC[0-last])*100/AUC[0-infinity]. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Elimination Half-life (t1/2) of Esketamine | Elimination half-life (t [1/2]) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Rate Constant (Lambda[z]) of Esketamine | Lambda(z) is first-order rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Absolute Bioavailability (Fabs) of Esketamine | The absolute bioavailability (Fabs) based on AUC(0-last) and AUC(0-inf) and estimated as 100*Test/Reference, where Test is defined as the pharmacokinetic parameters of oral esketamine and intranasal esketamine without clarithromycin and Reference is defined as intravenous esketamine. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Relative Bioavailability of Esketamine (Frel) | The relative bioavailability (Frel) based on Cmax, AUC(0-last), and AUC(0-inf) and estimated as 100*Test/Reference, where Test is defined as the pharmacokinetic parameters of intranasal esketamine and Reference is defined as intranasal esketamine + clarithromycin. | Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods | 
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Throughout the duration of study (approximately up to 98 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Healthy, Pharmacokinetics, Esketamine, JNJ-54135419