Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD: A Pilot Study
| Status: | Completed |
|---|---|
| Conditions: | Gastroesophageal Reflux Disease , Obesity Weight Loss |
| Therapuetic Areas: | Endocrinology, Gastroenterology |
| Healthy: | No |
| Age Range: | 6 - 17 |
| Updated: | 4/2/2016 |
| Start Date: | June 2013 |
| End Date: | July 2015 |
| Contact: | Jaylene D Weigel, RN,MSN,CCRC |
| Email: | jweigel@cmh.edu |
| Phone: | 816-701-1338 |
The Effect of Obesity on the Pharmacokinetics of Pantoprazole and CYP2C19 Activity in Children and Adolescents With GERD
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)
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)
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.
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.
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)
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