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

Sponsor
Children's Mercy Hospital Kansas City (Other)
Overall Status
Completed
CT.gov ID
NCT01887743
Collaborator
(none)
71
Enrollment
1
Location
1
Arm
28
Duration (Months)
2.5
Patients Per Site Per Month

Study Details

Study Description

Brief 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)

Condition or DiseaseIntervention/TreatmentPhase
Phase 1

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
71 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
The Effect of Obesity on the Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD
Study Start Date :
Jun 1, 2013
Actual Primary Completion Date :
Oct 1, 2015
Actual Study Completion Date :
Oct 1, 2015

Arms and Interventions

ArmIntervention/Treatment
Experimental: Pantoprazole

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.

Drug: Pantoprazole
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
  • Outcome Measures

    Primary Outcome Measures

    1. Pantoprazole Apparent Oral Clearance [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 [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 Outcome Measures

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    6 Years to 17 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes

    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)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Children's Mercy Hospital and ClinicsKansas CityMissouriUnited States64108

    Sponsors and Collaborators

    • Children's Mercy Hospital Kansas City

    Investigators

    • Principal Investigator: Craig Friesen, MD, Children's Mercy Hospital and Clinics

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Mercy Hospital Kansas City
    ClinicalTrials.gov Identifier:
    NCT01887743
    Other Study ID Numbers:
    • G130069PTZ-BT
    First Posted:
    Jun 27, 2013
    Last Update Posted:
    Dec 3, 2021
    Last Verified:
    Oct 1, 2021
    Keywords provided by Children's Mercy Hospital Kansas City
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleObeseOverweightNormal Weight
    Arm/Group DescriptionBMI for age at or above the 95th percentileBMI for age 85-94th percentileBMI for age <85th percentile
    Period Title: Overall Study
    STARTED201932
    COMPLETED191729
    NOT COMPLETED123

    Baseline Characteristics

    Arm/Group TitleNormal WeightOverweightObeseTotal
    Arm/Group DescriptionBMI10-84th percentile for ageBMI 85-94th percentile for ageBMI at or above 95th percentile for ageTotal of all reporting groups
    Overall Participants29171965
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    13.7
    (3.8)
    14.9
    (2.6)
    12.7
    (3.0)
    13.7
    (3.3)
    Sex: Female, Male (Count of Participants)
    Female
    14
    48.3%
    13
    76.5%
    13
    68.4%
    40
    61.5%
    Male
    15
    51.7%
    4
    23.5%
    6
    31.6%
    25
    38.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    6.9%
    0
    0%
    4
    21.1%
    6
    9.2%
    Not Hispanic or Latino
    27
    93.1%
    17
    100%
    15
    78.9%
    59
    90.8%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    29
    100%
    17
    100%
    17
    89.5%
    63
    96.9%
    BMI percentile for age (percentile for age) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentile for age]
    62.0
    (18.2)
    89.3
    (2.5)
    97.7
    (1.8)
    79.0
    (19.9)

    Outcome Measures

    1. Primary Outcome
    TitlePantoprazole Apparent Oral Clearance
    DescriptionPantoprazole 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).
    Time Frame8 hours

    Outcome Measure Data

    Analysis Population Description
    Only children with evaluable plasma samples (i.e., at least 85% of planned plasma samples collected) were included in this analysis (n=57).
    Arm/Group TitleNormal WeightOverweightObese
    Arm/Group DescriptionBMI10-84th percentile for ageBMI 85-94th percentile for ageBMI at or above 95th percentile for age
    Measure Participants281613
    Mean (Standard Deviation) [L/hr/kg]
    0.42
    (0.27)
    0.29
    (0.12)
    0.23
    (0.13)
    2. Primary Outcome
    TitleUnadjusted Pantoprazole Apparent Oral Clearance
    DescriptionPantoprazole 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).
    Time Frame8 hours

    Outcome Measure Data

    Analysis Population Description
    Only children with evaluable plasma samples (i.e., at least 85% of planned plasma samples collected) were included in this analysis (n=57).
    Arm/Group TitleNormal WeightOverweightObese
    Arm/Group DescriptionBMI10-84th percentile for ageBMI 85-94th percentile for ageBMI at or above 95th percentile for age
    Measure Participants281613
    Mean (Standard Deviation) [L/hr]
    20.4
    (14.2)
    18.7
    (7.43)
    16.8
    (8.55)
    3. Secondary Outcome
    TitlePrecision of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
    DescriptionChildren 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.
    Time Frame3 hours

    Outcome Measure Data

    Analysis Population Description
    The mean precision was calculated at 5 timepoints during the first 3 hours post-drug administration to test the breath test's ability to discriminate CYP2C19 EM from IM. All EM/IM children with evaluable breath test data were included as a single study group in this analysis.
    Arm/Group TitleBreath Test
    Arm/Group DescriptionChildren with evaluable breath data and the following CYP2C19 genotypes *1/*1, *1/17 (i.e., extensive metabolizer) and *1/*2 ,*2/*17 (i.e., intermediate metabolizer) were included in the breath test analyses (n=59) to assess how well the test could discriminate CYP2C19 extensive metablizers (EM) from intermediate metabolizers (IM).
    Measure Participants59
    30 minutes
    77.3
    (5.5)
    60 minutes
    77.7
    (5.0)
    90 minutes
    77.3
    (5.0)
    120 minutes
    77.8
    (5.1)
    180 minutes
    76.9
    (5.0)
    4. Secondary Outcome
    TitleRecall of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
    DescriptionChildren 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.
    Time Frame3 hours

    Outcome Measure Data

    Analysis Population Description
    The mean recall was calculated at 5 timepoints during the first 3 hours post-drug administration to test the breath test's ability to discriminate CYP2C19 EM from IM. All EM/IM children with evaluable breath test data were included as a single study group in this analysis.
    Arm/Group TitleBreath Test
    Arm/Group DescriptionChildren with evaluable breath data and the following CYP2C19 genotypes *1/*1, *1/17 (i.e., extensive metabolizer) and *1/*2 ,*2/*17 (i.e., intermediate metabolizer) were included in the breath test analyses (n=59) to assess how well the test could discriminate CYP2C19 extensive metablizers (EM) from intermediate metabolizers (IM).
    Measure Participants59
    30 minutes
    87.8
    (9.5)
    60 minutes
    93.6
    (7.9)
    90 minutes
    92.3
    (7.9)
    120 minutes
    92.4
    (7.5)
    180 minutes
    90.2
    (8.1)
    5. Secondary Outcome
    TitleHarmonic Mean of Precision and Recall (F1) of the Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
    DescriptionChildren 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.
    Time Frame3 hours

    Outcome Measure Data

    Analysis Population Description
    The mean F1 was calculated at 5 timepoints during the first 3 hours post-drug administration to test the breath test's ability to discriminate CYP2C19 EM from IM. All EM/IM children with evaluable breath test data were included as a single study group in this analysis.
    Arm/Group TitleBreath Test
    Arm/Group DescriptionChildren with evaluable breath data and the following CYP2C19 genotypes *1/*1, *1/17 (i.e., extensive metabolizer) and *1/*2 ,*2/*17 (i.e., intermediate metabolizer) were included in the breath test analyses (n=59) to assess how well the test could discriminate CYP2C19 extensive metablizers (EM) from intermediate metabolizers (IM).
    Measure Participants59
    30 minutes
    81.9
    (5.5)
    60 minutes
    84.7
    (4.7)
    90 minutes
    83.8
    (4.6)
    120 minutes
    84.3
    (4.5)
    180 minutes
    82.8
    (4.7)

    Adverse Events

    Time Frame8 hours during the PK study
    Adverse Event Reporting Description
    Arm/Group TitleNormal WeightOverweightObese
    Arm/Group DescriptionBMI10-84th percentile for ageBMI 85-94th percentile for ageBMI at or above 95th percentile for age
    All Cause Mortality
    Normal WeightOverweightObese
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/32 (0%) 0/19 (0%) 0/20 (0%)
    Serious Adverse Events
    Normal WeightOverweightObese
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/32 (0%) 0/19 (0%) 0/20 (0%)
    Other (Not Including Serious) Adverse Events
    Normal WeightOverweightObese
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/32 (0%) 0/19 (0%) 0/20 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleValentina Shakhnovich, MD
    OrganizationChildren's Mercy Kansas City
    Phone816-302-3068
    Emailvshakhnovich@cmh.edu
    Responsible Party:
    Children's Mercy Hospital Kansas City
    ClinicalTrials.gov Identifier:
    NCT01887743
    Other Study ID Numbers:
    • G130069PTZ-BT
    First Posted:
    Jun 27, 2013
    Last Update Posted:
    Dec 3, 2021
    Last Verified:
    Oct 1, 2021