Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD: A Pilot Study
Condition: Obesity; GERD
MeSH terms: Obesity
Intervention: Pantoprazole
Intervention description: 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.
Intervention MeSH terms: Pantoprazole
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 71.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GERD; Obesity; Pediatric; Pantoprazole; CYP2C19; Pharmacokinetic

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)
    

Eligibility criteria:

        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)