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

NCT01887743 | Completed Phase 1 Results DMC

• 1 other identifier: G130069PTZ-BT
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

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)

Conditions

Obesity; GERD

Keywords

GERD; Obesity; Pediatric; Pantoprazole; CYP2C19; Pharmacokinetic

Outcome Measures

Primary Outcomes (2)

• Pantoprazole Apparent Oral Clearance

  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).

  8 hours

• Unadjusted Pantoprazole Apparent Oral Clearance

  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).

  8 hours

Secondary Outcomes (3)

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

  3 hours

• Recall of Breath Test to Discriminate the CYP2C19 Extensive Metabolizer (EM) From Intermediate Metabolizer (IM) Phenotype

  3 hours

• 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

Study Arms (1)

Pantoprazole

EXPERIMENTAL

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

Interventions

Pantoprazole DRUG

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.

Also known as: Protonix

Pantoprazole

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead

Study Sites (1)

Children's Mercy Hospital and Clinics

Kansas City, Missouri, 64108, United States

Location

Related Publications (1)

• Shakhnovich V, Abdel-Rahman S, Friesen CA, Weigel J, Pearce RE, Gaedigk A, Leeder JS, Kearns GL. Lean body weight dosing avoids excessive systemic exposure to proton pump inhibitors for children with obesity. Pediatr Obes. 2019 Jan;14(1):10.1111/ijpo.12459. doi: 10.1111/ijpo.12459. Epub 2018 Sep 26.

  PMID: 30257076 DERIVED

MeSH Terms

Conditions

Obesity; Gastroesophageal Reflux

Interventions

Pantoprazole

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Valentina Shakhnovich, MD
• Organization: Children's Mercy Kansas City

vshakhnovich@cmh.edu

816-302-3068

Study Officials

• Craig Friesen, MD

  Children's Mercy Hospital and Clinics

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2013
• First Posted: June 27, 2013
• Study Start: June 1, 2013
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: December 3, 2021
• Results First Posted: December 3, 2021

Record last verified: 2021-10

Locations

US (1)