A Study to Investigate the Effect of Esomeprazole and the Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers

Study Overview
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Brief Summary
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This study will investigate the effect of food and the effect of esomeprazole on the pharmacokinetics (PK) of a single dose of balovaptan in healthy volunteers.

Official Title
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A Single-Center, Part-Randomized, Open-Label, Single-Dose, Three-Period, Crossover Study to Investigate the Effect of Esomeprazole and The Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Balovaptan
* Drug: Esomeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No evidence of any active or chronic disease Body mass index (BMI) between 18 and 32 kg/m2 inclusive, at screening For women of childbearing potential: if engaging in heterosexual activity, agreement to use at least two adequate forms of contraception during the entire study and for 90 days following the last dose of study drug For men: agreement to use contraceptive measures, and agreement to refrain from donating sperm Exclusion Criteria: Pregnancy or lactation (positive serum pregnancy test at screening or at admission) Any condition or disease detected during the medical interview/physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator In the opinion of the Investigator, any major illness within 4 weeks prior to the screening examination or any febrile illness within 1 week prior to screening. History of any clinically significant, as determined by the investigator, gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardiovascular, endocrinological, hematological, lymphatic, musculoskeletal, genitourinary, immunological, dermatological, or connective tissue or allergic disease, metabolic disorder, or cancer Signs and symptoms potentially indicative of peripheral neuropathy History or evidence of any medical condition potentially altering the absorption, distribution, metabolism, or elimination of drugs A history of clinically significant in the opinion of the Investigator hypersensitivity History or presence of clinically significant ECG abnormalities before study drug administration Clinically significant abnormalities in laboratory test results History of coagulopathies, bleeding disorders, or blood dyscrasias Current suicidal risk, in the opinion of the Investigator Unexplained syncope during the 6 months prior to screening or with presyncopal and/or syncopal symptoms during orthostatic challenge testing Current smoker or user of tobacco or nicotine-containing products or subjects who have smoked or used tobacco or nicotine-containing products within 3 months prior to first study drug administration Suspicion of or presence of a clinically relevant history of or current alcohol and/or other substance abuse or addiction. Alcohol consumption of >14 units per week for males and females Positive urine alcohol test or urine drug screen at screening or Day -1 of any treatment period Hormone replacement therapy if postmenopausal status cannot be ascertained from medical history or FSH levels Clinically relevant deviation from normal in the physical examination including vital signs, as determined by the investigator Positive result for HIV 1, HIV 2, hepatitis C virus antibody, or hepatitis B core (HBc) antibody. Participation in an investigational drug or device study within 4 weeks or 5 times the elimination half-life, whichever is longer, prior to first dosing, or within 5 months prior to first administration of study drug in case of a study with a biological, as calculated from the day of Follow-up visit from the previous study Donation of blood or plasma or significant blood loss within 3 months prior to screening Dietary restrictions that would prohibit the consumption of standardized meals or the highfat, high-calorie meal planned for this study Use of any prohibited medications or food before study start or subjects who do not agree to refrain from consuming prohibited medications or food during the study Conditions requiring concomitant medication during the study (including for dental conditions). Any prescribed systemic or topical medication within 4 weeks (or within 5 times the elimination half-life of the medication, whichever is longer) of the first administration of study drug Used any nonprescribed systemic or topical medication or herbal remedies within 7 days before the first study drug administration Received any medications known to chronically alter drug absorption or elimination processes within 4 weeks before the first administration of study drug Use of any drugs or substances, including herbal treatments such as St John's wort, that are known to be substrates, inducers, or inhibitors of CYP3A4 within 4 weeks before the first administration of study drug Use of any drugs or substances, including herbal treatments, such as fluoxetine, fluvoxamine, aspirin, norethisterone, rifampicin, etc that are known to be substrates, inducers, or inhibitors of CYP2C19 within 4 weeks before the first administration of study drug Subjects under judicial supervision, guardianship, or curatorship Poor venous access for blood sampling Participants who are intolerant to sucrose Previous exposure to balovaptan

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence ABC<br>In Period 1 participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose | Drug: Balovaptan<br>* Balovaptan will be administered after a high-fat, high-calorie meal (Treatment A), after a 10-hour fast (Treatment B), and after a 10-hour fast with esomeprazole 40 mg (Treatment C)<br>Drug: Esomeprazole<br>* Esomeprazole will be administered once daily for 6 days and with a single dose of balovaptan 1 hour after the fifth esomeprazole dose<br>|
| Experimental: Treatment sequence BAC<br>In Period 1 participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose | Drug: Balovaptan<br>* Balovaptan will be administered after a high-fat, high-calorie meal (Treatment A), after a 10-hour fast (Treatment B), and after a 10-hour fast with esomeprazole 40 mg (Treatment C)<br>Drug: Esomeprazole<br>* Esomeprazole will be administered once daily for 6 days and with a single dose of balovaptan 1 hour after the fifth esomeprazole dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Balovaptan | Maximum plasma concentration of Balovaptan is estimated using non-compartmental methods. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Mean Area Under the Concentration-Time Curve From Time Extrapolated to Infinity (AUC (0-inf)) of Balovaptan | Area under the plasma concentration-time curve (time 0 to infinity) of Balovaptan is estimated using non-compartmental methods from the concentration-time profiles. Percent extrapolation less than or equal to 20% is required to obtain a reliable AUC0-inf. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24h)) of Balovaptan | Area under the plasma concentration-time curve of Balovaptan from time 0 to 24 hours post-dose is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Balovaptan | Area under the concentration-time curve (time 0 to time of last quantifiable concentration) of Balovaptan is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time to Reach Cmax in Plasma (Tmax) of Balovaptan | Time to maximum plasma concentration of Balovaptan is defined as first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units and estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Last Quantifiable Concentration (Clast) of Balovaptan | Last quantifiable concentration is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time To the Last Quantifiable Concentration (Tlast) of Balovaptan | Time to last quantifiable concentration is based on last detectable concentration in the time curve. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time Between Dosing and Time of First Balovaptan Plasma Concentration (Tlag) | Time between dosing and time of first balovaptan plasma concentration is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Apparent Clearance (Cl/F) of Balovaptan | Apparent clearance is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Apparent Volume of Distribution (Vd/F) of Balovaptan | Apparent volume of distribution is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Elimination Phase Half-Life (T1/2) of Balovaptan | Terminal phase half-life expressed in time units is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Phase Rate Constant (λz) of Balovaptan | Terminal phase rate constant is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Plasma Concentrations of Balovaptan | Amount of Balovaptan in a given volume of plasma. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of M2 Metabolite | Maximum plasma concentration of M2 Metabolite is estimated using non-compartmental methods. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Maximum Plasma Concentration (Cmax) of M3 Metabolite | Maximum plasma concentration of M3 Metabolite is estimated using non-compartmental methods. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Maximum Plasma Concentration (Cmax) of Esomeprazole | Maximum plasma concentration of Esomeprazole is estimated using non-compartmental methods. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Area Under the Concentration-Time Curve From Time Extrapolated to Infinity (AUC (0-inf)) of M2 Metabolite | Area under the plasma concentration-time curve (time 0 to infinity) of M2 Metabolite is estimated using non-compartmental methods from the concentration-time profiles. Percent extrapolation less than or equal to 20% is required to obtain a reliable AUC0-inf. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Area Under the Concentration-Time Curve From Time Extrapolated to Infinity (AUC (0-inf)) of M3 Metabolite | Area under the plasma concentration-time curve (time 0 to infinity) of M3 Metabolite is estimated using non-compartmental methods from the concentration-time profiles. Percent extrapolation less than or equal to 20% is required to obtain a reliable AUC0-inf. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Area Under the Concentration-Time Curve From Time Extrapolated to Infinity (AUC (0-inf)) of Esomeprazole | Area under the plasma concentration-time curve (time 0 to infinity) of Esomeprazole is estimated using non-compartmental methods from the concentration-time profiles. Percent extrapolation less than or equal to 20% is required to obtain a reliable AUC0-inf. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24h)) of M2 Metabolite | Area under the plasma concentration-time curve of M2 Metabolite from time 0 to 24 hours post-dose is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24h)) of M3 Metabolite | Area under the plasma concentration-time curve of M3 Metabolite from time 0 to 24 hours post-dose is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of M2 Metabolite | Area under the concentration-time curve (time 0 to time of last quantifiable concentration) of M2 Metabolite is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of M3 Metabolite | Area under the concentration-time curve (time 0 to time of last quantifiable concentration) of M3 Metabolite is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Esomeprazole | Area under the concentration-time curve (time 0 to time of last quantifiable concentration) of Esomeprazole is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Time to Reach Cmax in Plasma (Tmax) of M2 Metabolite | Time to maximum plasma concentration of M2 Metabolite is defined as first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units and estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time to Reach Cmax in Plasma (Tmax) of M3 Metabolite | Time to maximum plasma concentration of M3 Metabolite is defined as first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units and estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time to Reach Cmax in Plasma (Tmax) of Esomeprazole | Time to maximum plasma concentration of Esomeprazole is defined as first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units and estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Last Quantifiable Concentration (Clast) of M2 Metabolite | Last quantifiable concentration is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Last Quantifiable Concentration (Clast) of M3 Metabolite | Last quantifiable concentration is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Last Quantifiable Concentration (Clast) of Esomeprazole | Last quantifiable concentration is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Time To the Last Quantifiable Concentration (Tlast) of M2 Metabolite | Time to last quantifiable concentration is based on last detectable concentration in the time curve. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time To the Last Quantifiable Concentration (Tlast) of M3 Metabolite | Time to last quantifiable concentration is based on last detectable concentration in the time curve. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Time To the Last Quantifiable Concentration (Tlast) of Esomeprazole | Time to last quantifiable concentration is based on last detectable concentration in the time curve. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Terminal Elimination Phase Half-Life (T1/2) of M2 Metabolite | Terminal phase half-life expressed in time units is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Elimination Phase Half-Life (T1/2) of M3 Metabolite | Terminal phase half-life expressed in time units is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Elimination Phase Half-Life (T1/2) of Esomeprazole | Terminal phase half-life expressed in time units is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Percentage of Patricipants With Adverse Events (AEs) |  | Randomization to end of study (up to approximately 7 weeks) | 
| Terminal Phase Rate Constant (λz) of M2 Metabolite | Terminal phase rate constant is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Phase Rate Constant (λz) of M3 Metabolite | Terminal phase rate constant is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Terminal Phase Rate Constant (λz) of Esomeprazole | Terminal phase half-life expressed in time units is estimated using non-compartmental methods from the concentration-time profiles. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose | 
| Plasma Concentrations of M2 Analyte | Amount of M2 Analyte in a given volume of plasma. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Plasma Concentrations of M3 Analyte | Amount of M3 Analyte in a given volume of plasma. | Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose | 
| Plasma Concentrations of Esomeprazole | Amount of Esomeprazole in a given volume of plasma. | Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose |