GERD, NAFLD, Pediatric Obesity
Conditions
Brief summary
This longitudinal study tests the hypothesis that obesity affects drug pharmacology of acid suppression medications in children.
Detailed description
The purpose of this research study is to see how the body breaks down certain medicines. Many medicines are broken down in the liver. The liver is an organ in the belly. A person's age, size, genetics (DNA), and the health of their liver decide how quickly the body breaks down medicines and how much medication a person needs to take. Everybody's liver has some fat in it, but the amount of fat is different from person to person. The purpose of this study is to see if the amount of fat in the liver affects how quickly acid suppression medications start and stop working and get removed from the body.
Interventions
DRUGLansoprazole
single-dose administration. Administered to a subset of participants who agreed to receive this drug upon enrollment.
DRUGPantoprazole
single-dose administration. Administered to a subset of participants who agreed to receive this drug upon enrollment.
DRUGMidazolam
single-dose administration. Administered to a subset of participants who agreed to receive this drug upon enrollment.
Sponsors
Children's Mercy Hospital Kansas City
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 21 Years
Healthy volunteers
Yes
Inclusion criteria
* 6-21 years of age * Obese and non-obese individuals * BMI ≥10th percentile for age (6-20 years of age) * BMI ≥18.5 (\>20 years of age) * Otherwise healthy; or otherwise healthy with diagnosis of GERD, NAFLD, chronic abdominal pain or obesity, according to report of medical history and/or review of the medical record * Receiving or not receiving pantoprazole or lansoprazole for routine medical care * MRI Hoop Test Clearance
Exclusion criteria
* Unable or unwilling to give written permission/assent/consent * For PO Study Drug: Any anatomic abnormality of the GI tract as defined by history, PE, or radiographic findings, including Bariatric surgery, Nissen fundoplication or equivalent surgery. * For IV Study Drug: Any anatomic abnormality of the GI tract as defined by history, PE, or radiographic findings, except Bariatric surgery, Nissen fundoplication or equivalent surgery. * For subjects undergoing weight management, treatment in the last 7 days with proton pump inhibitors omeprazole, esomeprazole, dexlansoprazole, or grapefruit juice. * For subjects not undergoing weight management, treatment in the last 7 days with medications known to clinically significantly inhibit (e.g., omeprazole, esomeprazole, fluoxetine, fluvoxamine, ketoconazole, ticlopidine, felbamate, trazodone, valproic acid, topiramate) or induce (e.g., phenobarbital, carbamazepine, phenytoin) CYP2C19; and those known at therapeutic doses to significantly inhibit (e.g., erythromycin, clarithromycin, grapefruit juice, verapamil, diltiazem, cimetidine, ketoconazole) or induce (e.g., oxcarbazepine, carbamazepine, phenytoin, phenobarbital, St. John's Wort, rifampin, rifapentine) or CYP3A4 activity in the last 7 days. * Unable to have blood drawn for the screening lab tests * Unable or unwilling to fast overnight prior to the study session * Unable to have blood drawn for the screening lab tests * If taking lansoprazole or pantoprazole for clinical purposes, unable or unwilling to abstain from that PPI for 3 days prior to PK visit when the PPI is not the same as the study drug for that PK visit * Metal in the body or any foreign bodies that precludes MRI sequencing * Claustrophobia * Exceeds 500lbs or 227 kg in Body Weight * Demonstrated adverse reaction to previous pantoprazole or PPI exposure * Impaired hepatic activity as determined by routine liver function testing and defined as values ≥ 5 times the age-specific upper limit of normal (ULN) for AST, ALT, total bilirubin \>2.0mg/dl, alkaline phosphatase ≥ 5 times the age-specific ULN * Impaired renal function defined as creatinine ≥ 3 times the age-specific ULN * Females of child-bearing age who are pregnant or breast-feeding * Any known infection with hepatitis B, C, or human immunodeficiency virus (HIV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma 1/2 Life (t1/2) | samples collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours after ingestion of study PPI drug | plasma elimination 1/2 life (t1/2) |
| Weight-adjusted Clearance | samples collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours after ingestion of study PPI drug | Weight-adjusted Drug plasma clearance (CL/F) |
| AUC | samples collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours after ingestion of study PPI drug | Plasma Area Under the Curve |
| Hepatic Fat Fraction | MRI obtained anytime within 30 days of PK visit | Hepatic Fat Fraction as measured by liver Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) |
| Tmax | samples collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours after ingestion of study PPI drug | Time to max plasma concentration |
| Cmax | samples collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours after ingestion of study PPI drug | Weight-Adjusted maximum plasma concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory Cytokines | Cytokines obtained from blood samples collected at pantoprazole PK study visit. | Mean and standard deviation of inflammatory cytokine levels measured from 58 of 71 participants who received pantoprazole. Cytokines include: INF-γ, IL-1β, IL-6. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKathryn Kyler, MD, MS
Children's Mercy Hospital Kansas City
Participant flow
Recruitment details
Subjects were recruited from the Gastroenterology clinic at Children's Mercy Kansas City. Subjects were also recruited from a pool of previous research participants, in the Divisions of Gastroenterology, Hepatology and Nutrition or Clinical Pharmacology, Toxicology and Therapeutic Innovation (the PI's home divisions), who had opted in to be contacted for future research opportunities. A notice was also be publicly displayed in the waiting areas of outpatient clinics at CMH.
Pre-assignment details
The study enrolled 76 participants to receive up to 3 drugs (lansoprazole n=48, pantoprazole n=71, midazolam n=29). Enrollment stopped prior to target enrollment completion for 1 drug (midazolam) as the original study PI left the institution. Some participants received ≥1 study drug: 13 received 1 study drug (either Lanso (5) or Panto (8), 54 received 2 drugs (Lanso+Panto (34) OR Panto+Midaz (20), and 9 received all 3 drugs. Those receiving lanso or panto returned for subsequent study visit.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 69 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| CYP2C19 Phenotype Data Missing | 7 Participants |
| CYP2C19 Phenotype Intermediate metabolizer | 21 Participants |
| CYP2C19 Phenotype Normal metabolizer | 25 Participants |
| CYP2C19 Phenotype Poor metabolizer | 2 Participants |
| CYP2C19 Phenotype Rapid metabolizer | 19 Participants |
| CYP2C19 Phenotype Ultrarapid metabolizer | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants |
| Race (NIH/OMB) More than one race | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 35 Participants |
| Weight Category No Obesity | 35 Participants |
| Weight Category Obesity | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 71 | 0 / 29 |
| other Total, other adverse events | 0 / 48 | 0 / 71 | 0 / 29 |
| serious Total, serious adverse events | 0 / 48 | 0 / 71 | 0 / 29 |
Outcome results
None listed