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Completed

NCT Number: NCT01887743

Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD: A Pilot Study

The World Health Organization has declared childhood obesity to be "one of the most serious public health challenges of the 21st century," (http://www.who.int/dietphysicalactivity/childhood). Given that obese children are generally excluded from clinical trials, little to no information exists regarding the impact of obesity on drug disposition and drug action, creating a gap in physicians' knowledge on how to appropriately select the dose of many critical medications (e.g., anticancer agents), so as to prevent toxicity associated with overdosing, while avoiding the harms of under-treatment. The proposed study will examine the effect of obesity on the metabolism of a commonly used medication, the proton pump inhibitor pantoprazole, by exploring the relationships between age, obesity, basal metabolic rate and genetic control of the enzyme primarily responsible for pantoprazole metabolism. We will also validate a simple breath test that can be used to predict pantoprazole dose requirement for obese children.

The study is designed to test the following experimental hypotheses:[13C]-pantoprazole pharmacokinetic parameters are not different between non-obese and obese children and adolescents, collectively (both age groups combined) or stratified by age group (SA 1) [13C]-pantoprazole pharmacokinetic parameters or DOB values (and thus, CYP2C19 activity) are not different between males and females (SA 1 & 2) [13C]-pantoprazole pharmacokinetic parameters and DOB (Delta over baseline) values (and thus, CYP2C19 activity) are independent of age over the age range of 6 to 17 years (SA 1 & 2) Obesity does not alter the relative contributions of CYP2C19-dependent and non-CYP2C19-dependent (i.e., CYP3A4) metabolism of pantoprazole, as measured by the urinary ratio of 4-hydroxy-pantoprazole to pantoprazole sulfone (SA 1 & 2) The [13C]-pantoprazole breath test, by determining DOB at discrete time point(s), is a non-invasive measure of CYP2C19 phenotype (SA 2) Clearance of pantoprazole (surrogate for CYP2C19 activity) is a function of REE in obese and non-obese children and adolescents (SA 3) Pantoprazole clearance (surrogate for CYP2C19 activity) is associated with fat distribution, as determined by waist-to-hip ratios (SA 3)

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Key information

Conditions

Obesity Body Weight Deglutition Disorders Digestive System Diseases Esophageal Diseases Esophageal Motility Disorders GERD Gastroesophageal Reflux Gastrointestinal Diseases Nutrition Disorders Nutritional and Metabolic Diseases Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

6 year–17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Children's Mercy Hospital and Clinics

Kansas City, Missouri, 64108, United States

About this study

As the pediatric obesity epidemic continues to rise, obesity-associated pathologic conditions, such as type II diabetes, hypertension and gastroesophageal reflux disease (GERD), become more prevalent, which, in turn, creates a need for a better understanding of the impact of obesity on drug disposition and response in pediatric patients with obesity. The following proposal is designed to address the hypothesis that obesity per se has significant effects on the pharmacokinetics of CYP2C19 substrates in children and adolescents. Pantoprazole, a proton pump inhibitor (PPI) frequently used in the treatment of GERD and related conditions, is ideally suited for such a study, given the predominant role of CYP2C19(Cytochrome P450 subtype 2C19) in its metabolism and its favorable safety and efficacy profile in pediatric medicine. The study of obesity on the activity of CYP2C19 is relevant, as it has not been previously studied in pediatrics and the enzyme catalyzes the biotransformation of over 20 drugs frequently used in pediatrics (eg., PPIs, selective serotonin re-uptake inhibitors). Moreover, knowledge of the CYP2C19 genotype and phenotype can be used to individualize drug treatment, making treatment safer and more effective for children. The primary objective of the proposed investigation is to evaluate the effect of obesity on the pharmacokinetics of pantoprazole in children and adolescents. The secondary objective is to assess the utility of the [13C]-pantoprazole breath test, a novel, non-invasive, in-vivo technique, as a surrogate biomarker of CYP2C19 activity in pediatric patients. In addition, the impact of non-genetic variables, such as resting energy expenditure (REE), on CYP2C19 activity will be investigated. The proposed research objectives will be achieved by administration of a single dose of oral [13C]-pantoprazole, a safe and stable non-radioactive isotope, to 100 patients (both male and female), including 50 obese (as defined by BMI >95th percentile) and 50 non-obese patients, between the ages of 6-17 years. Breath samples will be collected before, and for 8 hours after, [13C]-pantoprazole administration to quantify 13CO2(Carbon 13 dioxide)/12CO2(Carbon 12 dioxide) by infrared spectrometry. Simultaneously, repeated blood sampling will be used to measure pantoprazole, and its primary CYP2C19 catalyzed metabolite. Pantoprazole disposition will then be characterized from both breath sample and plasma level data and examined in association with important covariates (e.g., age, hip:waist ratio, BMI, REE, parent drug:metabolite ratio and CYP2C19 genotype) to test the experimental hypothesis. Data will be collected and analyzed by a team of highly experienced investigators representing the fields of gastroenterology, pediatric clinical pharmacology and the evolving field of obesity medicine.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Males and females between 6 and 17 years of age.
  • Pediatric patients who have a primary diagnosis of GERD or related symptoms, defined as one or more of the following: clinical symptoms consistent with GERD, a diagnosis of erosive esophagitis by endoscopy, esophageal biopsy with histopathology consistent with reflux esophagitis, abnormal pH probe study consistent with reflux esophagitis, or other test result consistent with GERD.
  • Non-obese: 10th - 84th percentile for BMI (50 subjects)
  • Overweight: greater than 85th percentile for BMI (50 subjects)
  • Provide written assent with parental permission

Exclusion criteria

  • Inability to have blood drawn for the screening lab tests
  • Current therapy with medications known to clinically significantly inhibit or to induce CYP2C19, such as phenytoin, oxcarbazepine, carbamazepine, and rifampicin
  • Inability or unwillingness to fast overnight prior to the study session
  • Established diagnosis of asthma with evidence of an exacerbation < 5 days before administration of the study article. Children with asthma that is well controlled on maintenance treatment will be eligible for enrollment to the study
  • Existence of metabolic disease
  • A demonstrated adverse reaction to previous pantoprazole or PPI exposure
  • Impaired hepatic activity as determined by routine liver function testing and defined as values greater than or equal to 3 times the age-specific upper limit of normal (ULN) for AST(aspartate amino transferase), ALT (alanine amino transferase), total bilirubin >2.0 mg/dl, alkaline phosphatase greater than or equal to 5 times the age-specific ULN
  • Impaired renal function defined as greater than or equal to 3 times the age-specific ULN
  • For females, a positive urine beta-human chorionic gonadotropin pregnancy test result
  • Any known infection with hepatitis B, C, or human immunodeficiency virus (HIV)

Treatment and study plan

Pantoprazole

Drug

This will be a single dose study where participants will receive 1.2mg/kg or no more than 100mg total one time dose as a liquid containing Carbon 13 labeled Pantoprazole with a final concentration of 4.0mg/mL.

Other names: Protonix

Primary outcomes

  1. Pantoprazole Apparent Oral Clearance

    Time frame: 8 hours

    Pantoprazole apparent oral drug clearance (CL/F) adjusted for weight for children with the most common CYP2C19 genotypes (i.e., *1/1, *1/17, *1/2, *2/17). Only children with evaluable plasma samples (i.e., at least 85% of planned plasma samples collected) were included in this analysis (n=57).

  2. Unadjusted Pantoprazole Apparent Oral Clearance

    Time frame: 8 hours

    Pantoprazole apparent oral drug clearance (CL/F), not adjusted for weight, for children with the most common CYP2C19 genotypes (i.e., *1/1, *1/17, *1/2, *2/17). Only children with evaluable plasma samples (i.e., at least 85% of planned plasma samples collected) were included in this analysis (n=57).

Secondary outcomes

  1. Precision of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype

    Time frame: 3 hours

    Children with common CYP2C19 genotypes (*1/*1, *1*17, *1/*2, *2/*17) who had evaluable breath test data (n=59) were included to evaluate the breath test's precision in discriminating the CYP2C19 Extensive Metabolizer (EM; *1/*1, *1*17) from the Intermediate Metabolizer (IM; *1/*2, *2/*17) phenotype in the first 3 hrs after study drug administration. A 3-hour window was chosen for convenience. A predictive model using breath test features (change in ratio of C12-to-C13 in exhaled CO2) was build and validated to predictphenotype for each child. We drew bootstrap samples, each stratified to preserve the observed prevalence of EM/IMs in the original cohort (n=59). Sampling with replacement left out 38% of the original sample to use as a test dataset to validate model performance. For each bootstrap sample, a 500-tree Extremely randomized Extra-Tree Forest was constructed after seeding. Using phenotypes predicted by the forest, predictive accuracy was assessed by computing precision.

  2. Recall of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype

    Time frame: 3 hours

    Children with common CYP2C19 genotypes (*1/*1, *1*17, *1/*2, *2/*17) who had evaluable breath test data (n=59) were included to evaluate the breath test's precision in discriminating the CYP2C19 Extensive Metabolizer (EM; *1/*1, *1*17) from the Intermediate Metabolizer (IM; *1/*2, *2/*17) phenotype in the first 3 hrs after study drug administration. A 3-hour window was chosen for convenience. A predictive model using breath test features (change in ratio of C12-to-C13 in exhaled CO2) was build and validated to predictphenotype for each child. We drew bootstrap samples, each stratified to preserve the observed prevalence of EM/IMs in the original cohort (n=59). Sampling with replacement left out 38% of the original sample to use as a test dataset to validate model performance. For each bootstrap sample, a 500-tree Extremely randomized Extra-Tree Forest was constructed after seeding. Using phenotypes predicted by the forest, predictive accuracy was assessed by computing recall.

  3. Harmonic Mean of Precision and Recall (F1) of the Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype

    Time frame: 3 hours

    Children with common CYP2C19 genotypes (*1/*1, *1*17, *1/*2, *2/*17) who had evaluable breath test data (n=59) were included to evaluate the breath test's precision in discriminating the CYP2C19 Extensive Metabolizer (EM; *1/*1, *1*17) from the Intermediate Metabolizer (IM; *1/*2, *2/*17) phenotype in the first 3 hrs after study drug administration. A 3-hour window was chosen for convenience. A predictive model using breath test features (change in ratio of C12-to-C13 in exhaled CO2) was build and validated to predictphenotype for each child. We drew bootstrap samples, each stratified to preserve the observed prevalence of EM/IMs in the original cohort (n=59). Sampling with replacement left out 38% of the original sample to use as a test dataset to validate model performance. For each bootstrap sample, a 500-tree Extremely randomized Extra-Tree Forest was constructed after seeding. Using phenotypes predicted by the forest, predictive accuracy was assessed by computing the F1.

Sponsors and collaborators

Lead sponsor

Children's Mercy Hospital Kansas City

Other

Registry information

Official study title

The Effect of Obesity on the Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD

Important dates

Study start
2013
Primary completion
2015
Study completion
2015
First posted
Jun 27, 2013
Registry last updated
Dec 3, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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