Gastroesophageal Reflux Disease
Conditions
Keywords
Gastrology, Vonoprazan, Gastroesophageal Reflux Disease, Children, GERD, Pharmacokinetics
Brief summary
The aim of this study is to evaluate the pharmacokinetic (PK) profile of vonoprazan (10 or 20 mg once daily \[QD\]) in children ≥ 6 to \< 12 years of age who have symptomatic Gastroesophageal Reflux Disease (GERD).
Interventions
DRUGVonoprazan
Administered orally
Sponsors
Phathom Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
1. The participant has a body weight within the 5th through 95th percentile by age, inclusive, as determined by the National Center for Health Statistics. 2. The participant must have a diagnosis of GERD prior to randomization and medical history of signs or symptoms of GERD for at least 3 months prior to screening, based on physical examination, current symptoms (eg, heartburn), or diagnostic tests (eg, pH or endoscopy). Notes in the medical records and/or other source documents, such as prior endoscopies, can be used to support the diagnosis and will be recorded in the electronic case report form (eCRF). 3. The participant has at least one moderate GERD symptom based on the GERD Symptom Assessment Investigator scale performed at screening. 4. The participant must be able to swallow study drug tablet with water. 5. Parent or legal guardian (ie, legally authorized representative \[LAR\]) is willing and able to complete the informed consent process and participants are able to comply with study procedures and visit schedule. 6. Female participants who have experienced menarche must have a negative pregnancy test and will be counseled on pregnancy avoidance.
Exclusion criteria
1. The participant has used prescription or non-prescription proton pump inhibitors (PPIs) or histamine-2 receptor antagonist (H2RAs) within 7 days prior to randomization or requires use during the Treatment Period. 2. The participant has used sucralfate, or antacids within 1 day prior to randomization or requires their use during the Treatment Period. 3. The participant has received other agents affecting digestive organs, including muscarinic antagonists (eg, hyoscyamine), prokinetics, oral anticholinergic agents, prostaglandins, bismuth from 30 days prior to Day 1 or requires their use during the course of the study. 4. The participant has received atazanavir sulfate or rilpivirine hydrochloride from 5 days prior to Day 1 or requires their use during the course of the study. 5. The participant has received any investigational compound (including vonoprazan) within 30 days prior to the start of the Screening Period. 6. The participant is an immediate family member or is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, child, sibling) or participant may have consented under duress. 7. The participant requires hospitalization or has surgery scheduled during the course of the study or has undergone major surgical procedures within 30 days prior to the Screening Period. 8. The participant has undergone prior gastrointestinal surgeries. 9. The participant has any abnormal laboratory test values that are considered clinically significant in the opinion of the investigator during the Screening Period. 10. The participant has a history of hypersensitivity or allergies to vonoprazan (including the formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropylcellulose, fumaric acid, ascorbic acid, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, and titanium dioxide, or red or yellow ferric oxide). 11. The participant has used any prescription or over-the-counter medications (including herbal or nutritional supplements), other than those already excluded in criteria 1 to 5 above, within 14 days before the first dose of study drug or throughout the study. That is, unless the medication(s) is permitted by the sponsor following a review of available data which confirms concomitant administration of the medication is unlikely to affect either the safety of the participant or the pharmacokinetics of vonoprazan. 12. The participant has consumed grapefruit or grapefruit juice, Seville orange or Seville orange-containing products (eg, marmalade), or other 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. 13. The participant has positive results at screening for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus (HCV). 14. The participant has severe renal impairment (estimated glomerular filtration rate \< 30 mL/min). 15. The participant has moderate to severe hepatic impairment (Child-Pugh Class B and Child-Pugh Class C). 16. The participant has any of the following abnormal laboratory test values at the start of the Screening Period: 1. Creatinine levels: \>0.8 mg/dL (\>70 μmol/L). 2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2 × the upper limit of normal (ULN) or total bilirubin \>2 × ULN (except participants with Gilbert Syndrome). 17. In the opinion of the investigator, the participant is not suitable for entry into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Drug Concentration at Steady-state (Cmax,ss) of Vonoprazan | Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose | Plasma pharmacokinetic (PK) parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14. |
| Area Under the Plasma Concentration-time Curve During the Dosing Interval τ at Steady State (AUCτ,ss) of Vonoprazan | Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose | Plasma PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14. |
| Apparent Oral Clearance (CL/F) at Steady State of Vonoprazan | Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose | Oral PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14. |
| Apparent Central Volume of Distribution (Vz/F) at Steady State of Vonoprazan | Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose | Plasma PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14. |
Countries
United States
Participant flow
Recruitment details
A total of 22 participants were enrolled at 6 study sites in the United States between November 2023 and April 2024.
Participants by arm
| Arm | Count |
|---|---|
| Vonoprazan 10 mg Participants received vonoprazan 10 mg QD for 14 days. | 11 |
| Vonoprazan 20 mg Participants received vonoprazan 20 mg QD for 14 days. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Voluntary Withdrawal | 0 | 2 |
Baseline characteristics
| Characteristic | Vonoprazan 20 mg | Total | Vonoprazan 10 mg |
|---|---|---|---|
| Age, Continuous | 8.6 years STANDARD_DEVIATION 1.69 | 8.9 years STANDARD_DEVIATION 1.78 | 9.1 years STANDARD_DEVIATION 1.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 15 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 1 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Apparent Central Volume of Distribution (Vz/F) at Steady State of Vonoprazan
Plasma PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14.
Time frame: Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose
Population: PK Set: includes all participants who received at least 1 dose of study drug and had sufficient concentration data to support accurate estimation of at least 1 PK parameter.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vonoprazan 10 mg | Apparent Central Volume of Distribution (Vz/F) at Steady State of Vonoprazan | 491 liters |
| Vonoprazan 20 mg | Apparent Central Volume of Distribution (Vz/F) at Steady State of Vonoprazan | 444 liters |
Primary
Apparent Oral Clearance (CL/F) at Steady State of Vonoprazan
Oral PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14.
Time frame: Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose
Population: PK Set: includes all participants who received at least 1 dose of study drug and had sufficient concentration data to support accurate estimation of at least 1 PK parameter.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vonoprazan 10 mg | Apparent Oral Clearance (CL/F) at Steady State of Vonoprazan | 125 L/h |
| Vonoprazan 20 mg | Apparent Oral Clearance (CL/F) at Steady State of Vonoprazan | 118 L/h |
Primary
Area Under the Plasma Concentration-time Curve During the Dosing Interval τ at Steady State (AUCτ,ss) of Vonoprazan
Plasma PK parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14.
Time frame: Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose
Population: PK Set: includes all participants who received at least 1 dose of study drug and had sufficient concentration data to support accurate estimation of at least 1 PK parameter.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vonoprazan 10 mg | Area Under the Plasma Concentration-time Curve During the Dosing Interval τ at Steady State (AUCτ,ss) of Vonoprazan | 88.3 h*ng/mL |
| Vonoprazan 20 mg | Area Under the Plasma Concentration-time Curve During the Dosing Interval τ at Steady State (AUCτ,ss) of Vonoprazan | 251 h*ng/mL |
Primary
Maximum Drug Concentration at Steady-state (Cmax,ss) of Vonoprazan
Plasma pharmacokinetic (PK) parameters were estimated using a non-linear mixed effects model and were determined from the concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled or nominal sampling times, were used in all computations using sampling time. Data presented based on collections on both Day 7 and Day 14.
Time frame: Day 7: pre-dose, 0.5 to 1.5 hour and 2.5 to 3.5 hours post dose; Day 14: pre-dose, 1 to 2 hours and 3 to 4 hours post dose
Population: PK Set: includes all participants who received at least 1 dose of study drug and had sufficient concentration data to support accurate estimation of at least 1 PK parameter.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vonoprazan 10 mg | Maximum Drug Concentration at Steady-state (Cmax,ss) of Vonoprazan | 16.2 ng/mL |
| Vonoprazan 20 mg | Maximum Drug Concentration at Steady-state (Cmax,ss) of Vonoprazan | 42.1 ng/mL |