Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD: A Pilot Study
Condition: Obesity; GERD
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 1

Summary: 
      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)
    

Detailed description: 
      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.
    

Intervention name(s): Pantoprazole
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Protonix
Intervention MeSH terms: Pantoprazole
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: GERD; Obesity; Pediatric; Pantoprazole; CYP2C19; Pharmacokinetic