PK Study With Pantoprazole in Obese Children and Adolescents

Conditions

Gastroesophageal Reflux Disease

Keywords

obese, children, adolescents, GERD, pharmacokinetic

Brief summary

Multicenter, comparative single-dose pharmacokinetic (PK) study

Detailed description

Evaluate the pharmacokinetics of pantoprazole in obese children and adolescents with gastroesophageal reflux disease (GERD) following administration of an oral dose of pantoprazole.

Elizabeth J. Thompson, Angela Jeong, Victória Etges Helfer, Valentina Shakhnovich, Andrea N. Edginton et al. (10 authors)

CPT Pharmacometrics & Systems Pharmacology2024-06-045 citations

10.1002/psp4.13167

Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures.

Shakhnovich V, Smith PB, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL, Best Pharmaceuticals for Children Act – Pediatric Trials Network.

2018-02-0125 citations

10.1016/j.jpeds.2017.10.011

Interventions

DRUGPantoprazole

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

6 Years to 17 Years

Healthy volunteers

No

Inclusion criteria

1. Participant is between 6 and 17 (inclusive) years of age at the time of consent 2. BMI ≥95th percentile 3. Diagnosis of GERD established prior to 7 days before receipt of study drug dose defined as 1 or more of the following: 1. clinical symptoms consistent with GERD as determined by the investigator 2. a diagnosis of erosive esophagitis by endoscopy 3. esophageal biopsy with histopathology consistent with reflux esophagitis 4. abnormal pH-metry consistent with reflux esophagitis 5. other test result consistent with GERD 4. Written informed consent from the parent or legally authorized representative/guardian and participant assent per local IRB recommendation of age-appropriate consent and assent requirements

Exclusion criteria

1. Use of pantoprazole, lansoprazole, omeprazole, esomeprazole or rabeprazole within 48 hours prior to dose of study drug 2. Use of fluoxetine, fluvoxamine, ketoconazole, ticlopidine, felbamate, topiramate, valproic acid, phenobarbital, carbamazepine, erythromycin, clarithromycin, grapefruit juice, verapamil, diltiazem, cimetidine, St. John's Wort, rifampin, rifapentine within seven days prior to dose of study drug 3. Consumption of food after midnight on the day of the baseline visit 4. Symptomatic asthma 5. Type I diabetes 6. History of adverse reaction to PPI 7. Impaired hepatic activity as defined as any of the following: AST ≥150 IU/L, ALT ≥150 IU/L, total bilirubin ≥2.0 mg/dl, or alkaline phosphatase ≥600 IU/L 8. Serum creatinine ≥2.0 mg/dL 9. For females of childbearing potential, a positive pregnancy test result 10. Known infection with hepatitis B, C, or HIV 11. Any other condition that, in the opinion of the principal investigator, makes participation unadvised or unsafe.

Design outcomes

Primary

Measure	Time frame	Description
Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (Vd/F).	pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours	The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report Vd/F TBW.
Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (Cmax).	pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours	The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report Cmax.
Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (Tmax).	pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours	The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report Tmax.
PK Sampling	Pre-dose (within 30 minutes), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (±10 minutes) after dosing	Total number of fresh plasma samples (all participants)
Drug Concentration in Plasma Samples	Pre-dose (within 30 minutes), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (±10 minutes) after dosing	Concentration of panto in plasma and concentration of panto sulfone in plasma
Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (AUC).	pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours	The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report AUC TBW.
Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (CL/F).	pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours	The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report CL/F TBW.

Secondary

Measure	Time frame	Description
The CYP2C19 Genotype and Its Association With CYP2C19 Phenotype	0, 1, 2, 3, 4, 6, 8, 12 hours post-dose	To examine the association of CYP2C19 genotype and its association with CYP2C19 phenotypes. To characterize the ability of the CYP2C19 genotype to predict pantoprazole plasma clearance, a correlation with CYP2C19 phenotype was explored using both standard linear and nonlinear regression techniques and their respective tests for significance and goodness of fit. In addition, the impact of all covariates on pantoprazole systemic exposure and apparent plasma clearance (e.g., demographic determinants of extent of obesity such as the waist:hip ratio, CYP2C19 genotype, BMI, and REE) was explored using validated population-based PK methods (NONMEM).

Countries

United States

Participant flow

Recruitment details

The first participant for this study began on 8-July-2014. The last participant to complete the study was on 13-September-2015.

Participants by arm

Arm	Count
Pantoprazole 6-11 Year Old The study design included a screening visit (0-31days prior to baseline), during which informed consent was obtained and blood was collected for isolation of DNA for genotyping. During the Baseline Visit (Day 1) included REE measurement (before drug administration using a MedGem indirect calorimeter), study drug administration, and PK evaluation. The MedGem measures oxygen consumption (VO2) to determine resting metabolic rate. Study drug was then administered orally, and repeated blood samples of 1.0 ml each were collected at pre-dose (within 30 minutes), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (±10 minutes) after dosing. For those participants with the PM CYP2C19 genotype, an additional PK sample was to be obtained at 12 hours after dosing. Between Day 10 and Day 13 after the Baseline Visit, investigators conducted a follow-up call to assess participants' general wellness and to collect Adverse Event (AE) information.	19
Pantoprazole 12-17 Year Old The study design included a screening visit (0-31days prior to baseline), during which informed consent was obtained and blood was collected for isolation of DNA for genotyping. During the Baseline Visit (Day 1) included REE measurement (before drug administration using a MedGem indirect calorimeter), study drug administration, and PK evaluation. The MedGem measures oxygen consumption (VO2) to determine resting metabolic rate. Study drug was then administered orally, and repeated blood samples of 1.0 ml each were collected at pre-dose (within 30 minutes), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (±10 minutes) after dosing. For those participants with the PM CYP2C19 genotype, an additional PK sample was to be obtained at 12 hours after dosing. Between Day 10 and Day 13 after the Baseline Visit, investigators conducted a follow-up call to assess participants' general wellness and to collect Adverse Event (AE) information.	22
Total	41

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	2	0

Baseline characteristics

Characteristic	Pantoprazole 6-11 Year Old	Pantoprazole 12-17 Year Old	Total
Age, Continuous	10 years STANDARD_DEVIATION 2	15 years STANDARD_DEVIATION 2	12 years STANDARD_DEVIATION 3
BMI	28.0 kg/m^2 STANDARD_DEVIATION 5.8	35.0 kg/m^2 STANDARD_DEVIATION 5	31.7 kg/m^2 STANDARD_DEVIATION 6.4
BMI Percentile	98 percentile STANDARD_DEVIATION 1	98 percentile STANDARD_DEVIATION 1	98 percentile STANDARD_DEVIATION 1
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	3 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants	19 Participants	35 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	2 Participants
Height	144.4 cm STANDARD_DEVIATION 13.9	166.6 cm STANDARD_DEVIATION 7.4	156.3 cm STANDARD_DEVIATION 15.6
Height Percentile	65.3 percentile STANDARD_DEVIATION 28.9	60.9 percentile STANDARD_DEVIATION 29.7	62.9 percentile STANDARD_DEVIATION 29.1
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	7 Participants	6 Participants	13 Participants
Race (NIH/OMB) More than one race	2 Participants	1 Participants	3 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	3 Participants	4 Participants
Race (NIH/OMB) White	8 Participants	12 Participants	20 Participants
Region of Enrollment United States	19 participants	22 participants	41 participants
Sex: Female, Male Female	12 Participants	11 Participants	23 Participants
Sex: Female, Male Male	7 Participants	11 Participants	18 Participants
Weight	60.5 kg STANDARD_DEVIATION 23.7	97.9 kg STANDARD_DEVIATION 19.6	80.6 kg STANDARD_DEVIATION 28.5
Weight Percentile	96.8 percentile STANDARD_DEVIATION 3.6	97.9 percentile STANDARD_DEVIATION 3.4	97.4 percentile STANDARD_DEVIATION 3.5

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 22
other Total, other adverse events	1 / 19	6 / 22
serious Total, serious adverse events	0 / 19	0 / 22

Outcome results

Primary

Drug Concentration in Plasma Samples

Concentration of panto in plasma and concentration of panto sulfone in plasma

Time frame: Pre-dose (within 30 minutes), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (±10 minutes) after dosing

Population: All participants with evaluable data

Arm	Measure	Group	Value (MEAN)	Dispersion
Pantoprazole 6-11 Year Old	Drug Concentration in Plasma Samples	Pantoprazole	1558 ng/ml	Standard Deviation 1584.6
Pantoprazole 6-11 Year Old	Drug Concentration in Plasma Samples	Pantoprazole Sulfone	94.7 ng/ml	Standard Deviation 49.1
Pantoprazole 12-17 Year Old	Drug Concentration in Plasma Samples	Pantoprazole	1626.1 ng/ml	Standard Deviation 1545.2
Pantoprazole 12-17 Year Old	Drug Concentration in Plasma Samples	Pantoprazole Sulfone	88.7 ng/ml	Standard Deviation 36.8

Primary

Pharmacokinetic Analysis in Obese Children After One Single Oral Dose of Pantoprazole (AUC).

The pharmacokinetic blood samples will be 1.0 ml each and collected at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours after receiving one dose of Pantoprazole study drug. For those subjects with the poor metabolizer CYP2C19 genotype, an additional PK sample will be obtained at 12 hours after dosing. Here we report AUC TBW.

Time frame: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, & 8 hours