Healthy Volunteers
Conditions
Keywords
vonoprazan, midazolam
Brief summary
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
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.).
Interventions
DRUGVonoprazan
20 mg tablets administered orally
DRUGMidazolam
2 mg syrup administered orally
Sponsors
Phathom Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. The participant is male or female 18 to 45 years of age, inclusive, at Screening. 2. The participant has a body mass index (BMI) 18 to 30 kg/m2, inclusive, and body weight \>50 kg at Screening. 3. 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. 4. 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). 5. Female participants must have a negative pregnancy test at Screening and Check-in. 6. The participant agrees to comply with all protocol requirements. 7. The participant is able to provide written informed consent.
Exclusion criteria
1. 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. 2. 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. 3. 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. 4. The participant has serum creatinine \>1.2 mg/dL or blood urea nitrogen \>20 mg/dL at Screening or Check-in. 5. The participant has any acute laboratory abnormality at Screening that precludes participation in the study, in the opinion of the investigator. 6. 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). 7. 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. 8. 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. 9. 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. 10. 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. 11. 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. 12. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at Screening or Check-in. 13. The subject is involved in strenuous activity or contact sports within 24 hours before the first dose of study drug or throughout the study. 14. The subject has donated blood or blood products \>450 mL within 30 days before the first dose of study drug. 15. 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). 16. The subject has received study drug in another investigational study within 30 days of dosing. 17. 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. 18. The subject has a history of acute narrow-angle glaucoma. 19. In the opinion of the investigator, the subject is not suitable for entry into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Midazolam | 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 | AUC0-t was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Midazolam | 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 | AUC0-inf was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. |
| Maximum Observed Plasma Concentration (Cmax) of Midazolam | 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 | Cmax was measured for midazolam alone on Day 1 and for midazolam administered with vonoprazan on Day 9. |
Countries
United States
Participant flow
Recruitment details
20 participants were enrolled at a single study center in the United States.
Pre-assignment details
32 participants were screened, 12 of which were screen failures. The remaining 20 were enrolled and received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants were administered single oral doses of 2 mg of midazolam syrup on Day 1 and Day 9 and BID oral doses of 20 mg vonoprazan tablets on Days 2 through 10. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 7.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 4 / 20 | 2 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
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.
Time frame: 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
Population: The PK population included participants who received at least one dose of study drug and had sufficient concentration data to support accurate estimation of at least one PK parameter. Participants who experienced vomiting within two times the median time to maximum observed plasma concentration (Tmax) after midazolam dosing were excluded from the PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone | Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Midazolam | 25.5 Nanogram Hours per Milliliter (ng•h/mL) | Standard Deviation 9 |
| Midazolam With Vonoprazan | Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Midazolam | 52.3 Nanogram Hours per Milliliter (ng•h/mL) | Standard Deviation 39.8 |
Comparison: A linear mixed model with treatment as a fixed effect and participant as a random effect was performed on the natural log-transformed values to assess the effect of vonoprazan on the PK of midazolam.90% CI: [150.6, 236.9]
Primary
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.
Time frame: 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
Population: The pharmacokinetics (PK) population included participants who received at least one dose of study drug and had sufficient concentration data to support accurate estimation of at least one PK parameter. Participants who experienced vomiting within two times the median time to maximum observed plasma concentration (Tmax) after midazolam dosing were excluded from the PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Midazolam | 24.2 Nanogram Hours per Milliliter (ng•h/mL) | Standard Deviation 8.76 |
| Midazolam With Vonoprazan | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Midazolam | 50.7 Nanogram Hours per Milliliter (ng•h/mL) | Standard Deviation 39.8 |
Comparison: A linear mixed model with treatment as a fixed effect and participant as a random effect was performed on the natural log-transformed values to assess the effect of vonoprazan on the PK of midazolam.90% CI: [152.8, 242.4]
Primary
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.
Time frame: 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
Population: The PK population included participants who received at least one dose of study drug and had sufficient concentration data to support accurate estimation of at least one PK parameter. Participants who experienced vomiting within two times the median time to maximum observed plasma concentration (Tmax) after midazolam dosing were excluded from the PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam Alone | Maximum Observed Plasma Concentration (Cmax) of Midazolam | 10.3 Nanograms per Milliliter (ng/mL) | Standard Deviation 3.61 |
| Midazolam With Vonoprazan | Maximum Observed Plasma Concentration (Cmax) of Midazolam | 20.3 Nanograms per Milliliter (ng/mL) | Standard Deviation 9.55 |
Comparison: A linear mixed model with treatment as a fixed effect and participant as a random effect was performed on the natural log-transformed values to assess the effect of vonoprazan on the PK of midazolam.90% CI: [160.5, 233.1]