Evaluation of Effect of Vonoprazan on Midazolam Pharmacokinetics in Healthy Participants

Study Overview
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Brief Summary
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To determine the time-dependent inhibition potential of repeated doses of oral vonoprazan on the pharmacokinetics (PK) of a single oral dose of midazolam, a sensitive cytochrome P450 3A4 (CYP3A4) substrate, in healthy participants.

Detailed Description
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This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Official Title
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An Open-Label, Fixed Sequence, Clinical Drug Interaction Study to Evaluate the Time-Dependent Inhibition Potential of Vonoprazan on a Sensitive CYP3A4 Substrate, Midazolam, in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Vonoprazan
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant is male or female 18 to 45 years of age, inclusive, at Screening. The participant has a body mass index (BMI) 18 to 30 kg/m2, inclusive, and body weight >50 kg at Screening. The participant is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and physical examination findings at Screening. Female participants of childbearing potential who may be sexually active with a non-sterilized male partner must use an acceptable method of birth control (ie, diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence) from the signing of informed consent until 4 weeks after the last dose of study drug or be surgically sterile (ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as amenorrhea for 12 consecutive months and documented plasma follicle-stimulating hormone [FSH] level >40 IU/mL). Female participants must have a negative pregnancy test at Screening and Check-in. The participant agrees to comply with all protocol requirements. The participant is able to provide written informed consent. Exclusion Criteria: The participant has a history of any clinically significant neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, hematological, or endocrine disease or other abnormality that may affect the ability of the subject to participate in the study. The participant has a positive test result for coronavirus disease 2019 (COVID-19), hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2 antibodies at Screening. The participant has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN) or total bilirubin >1.5 × ULN (with the exception of Gilbert's syndrome) at Screening or Check-in. The participant has serum creatinine >1.2 mg/dL or blood urea nitrogen >20 mg/dL at Screening or Check-in. The participant has any acute laboratory abnormality at Screening that precludes participation in the study, in the opinion of the investigator. The participant has a current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome and asymptomatic gallstones). The subject has used any prescription (excluding hormonal birth control) or over-the-counter medications (including CYP3A4 inducers) except paracetamol (up to 2 g per day), including herbal or nutritional supplements, within 14 days (or 5 half-lives) before the first dose of study drug or throughout the study. The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville orange-containing products (eg, marmalade), or food products that may be CYP3A4 inhibitors (eg, vegetables from the mustard green family [kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled meats) within 7 days (or 5 half-lives) before the first dose of study drug or throughout the study. The subject has consumed caffeine or xanthine-containing products within 48 hours (or 5 half-lives) before the first dose of study drug or throughout the study. The subject is a smoker or has used nicotine or nicotine-containing products (eg, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) within 6 months before the first dose of study drug. The subject has a history of alcohol abuse or drug addiction within the last year, excessive alcohol consumption (regular alcohol intake >21 units per week for male subjects and >14 units of alcohol per week for female subjects; 1 unit is equal to approximately 1/2 pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at Screening or Check-in. The subject is involved in strenuous activity or contact sports within 24 hours before the first dose of study drug or throughout the study. The subject has donated blood or blood products >450 mL within 30 days before the first dose of study drug. The subject has a history of relevant drug and/or food allergies (ie, allergy to midazolam, vonoprazan, or their excipients [including cherries] or any significant food allergy that could preclude a standard diet in the clinical unit). The subject has received study drug in another investigational study within 30 days of dosing. Female subject is pregnant or lactating, intends to become pregnant before, during, or within 4 weeks after participating in this study, or intends to donate ova during this time period. The subject has a history of acute narrow-angle glaucoma. In the opinion of the investigator, the subject is not suitable for entry into the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midazolam single doses / Vonoprazan multiple doses<br>Single oral doses of 2 mg of midazolam syrup on Day 1 and Day 9 and twice daily (BID) doses of 20 mg vonoprazan oral tablets on Days 2 through 10 | Drug: Vonoprazan<br>* 20 mg tablets administered orally<br>Drug: Midazolam<br>* 2 mg syrup administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Midazolam | AUC0-t was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. | Day 1 (midazolam alone): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose; Day 9 (midazolam and vonoprazan): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Midazolam | AUC0-inf was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. | Day 1 (midazolam alone): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose; Day 9 (midazolam and vonoprazan): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Midazolam | Cmax was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. | Day 1 (midazolam alone): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose; Day 9 (midazolam and vonoprazan): Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vonoprazan, midazolam