Effect of Obesity on Proton Pump Inhibitors

Study Overview
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Brief Summary
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This longitudinal study tests the hypothesis that obesity affects drug pharmacology of acid suppression medications in children.

Detailed Description
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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.

Official Title
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Physiologic Determinants of PPI Disposition in Children

Conditions
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Pediatric Obesity, NAFLD, GERD

Intervention / Treatment
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* Drug: Pantoprazole
* Drug: Midazolam injection


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 21 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: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: In Weight Management Program<br>Evaluate the effect of liver fat on pharmacology of PPI's, and if applicable midazolam | Drug: Pantoprazole<br>* single-dose administration<br>Drug: Midazolam injection<br>* single-dose administration<br>|
| Experimental: Not in Weight Management Program<br>Evaluate the effect of liver fat on drug metabolism of PPI's, and if applicable midazolam | Drug: Pantoprazole<br>* single-dose administration<br>Drug: Midazolam injection<br>* single-dose administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma pharmacokinetics of pantoprazole | plasma maximum peak concentration (Cmax) | 5 years | 
| plasma pharmacokinetics of pantoprazole | area under the concentration time curve (AUC) | 5 years | 
| plasma pharmacokinetics of pantoprazole | time to maximum peak concentration (tmax) | 5 years | 
| plasma pharmacokinetics of pantoprazole | half-life (t 1/2) | 5 years | 
| plasma pharmacokinetics of pantoprazole | volume of distribution (Vd) | 5 years | 
| plasma pharmacokinetics of pantoprazole | clearance (CL) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacodynamics | concentration of gastric acid using pH probe test | 5 years | 
| safety of pantoprazole: incidence of reported and gastrointestinal adverse events | incidence of reported and gastrointestinal adverse events | 5 years | 
| pharmacokinetics of midazolam, if medication received to ease discomfort of pH probe study | plasma concentrations of midazolam | 5 years | 
| urinary metabolites | urine concentrations of pantoprazole and midazolam and their metabolites | 5 years |