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)
• Enrollment: 71
• Location: 1
• Arm: 1
• Duration (Months): 28
• Patients Per Site Per Month: 2.5

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 Disease	Intervention/Treatment	Phase
Obesity; GERD	Drug: Pantoprazole	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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108

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: GERD; Obesity; Pediatric; Pantoprazole; CYP2C19; Pharmacokinetic
• Additional relevant MeSH terms: Obesity; Pantoprazole

Study Results

Participant Flow

Arm/Group Title	Obese	Overweight	Normal Weight
Arm/Group Description	BMI for age at or above the 95th percentile	BMI for age 85-94th percentile	BMI for age <85th percentile
Period Title: Overall Study
STARTED	20	19	32
COMPLETED	19	17	29
NOT COMPLETED	1	2	3

Baseline Characteristics

Arm/Group Title	Normal Weight	Overweight	Obese	Total
Arm/Group Description	BMI10-84th percentile for age	BMI 85-94th percentile for age	BMI at or above 95th percentile for age	Total of all reporting groups
Overall Participants	29	17	19	65
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

Title	Pantoprazole Apparent Oral Clearance
Description	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).
Time Frame	8 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 Title	Normal Weight	Overweight	Obese
Arm/Group Description	BMI10-84th percentile for age	BMI 85-94th percentile for age	BMI at or above 95th percentile for age
Measure Participants	28	16	13
Mean (Standard Deviation) [L/hr/kg]	0.42 (0.27)	0.29 (0.12)	0.23 (0.13)

2. Primary Outcome

Title	Unadjusted Pantoprazole Apparent Oral Clearance
Description	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).
Time Frame	8 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 Title	Normal Weight	Overweight	Obese
Arm/Group Description	BMI10-84th percentile for age	BMI 85-94th percentile for age	BMI at or above 95th percentile for age
Measure Participants	28	16	13
Mean (Standard Deviation) [L/hr]	20.4 (14.2)	18.7 (7.43)	16.8 (8.55)

3. Secondary Outcome

Title	Precision of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
Description	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.
Time Frame	3 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 Title	Breath Test
Arm/Group Description	Children 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 Participants	59
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

Title	Recall of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
Description	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.
Time Frame	3 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 Title	Breath Test
Arm/Group Description	Children 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 Participants	59
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

Title	Harmonic Mean of Precision and Recall (F1) of the Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype
Description	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.
Time Frame	3 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 Title	Breath Test
Arm/Group Description	Children 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 Participants	59
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 Frame	8 hours during the PK study
Arm/Group Title	Normal Weight		Overweight		Obese
Arm/Group Description	BMI10-84th percentile for age		BMI 85-94th percentile for age		BMI at or above 95th percentile for age
All Cause Mortality
	Normal Weight		Overweight		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/19 (0%)		0/20 (0%)
Serious Adverse Events
	Normal Weight		Overweight		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Normal Weight		Overweight		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (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.