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PEDIATRICS |
From Children's Mercy Hospitals and Clinics and the University of Missouri, Kansas City, Kansas (Dr Kearns, Dr Daniel, Dr Gaedigk); the Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio (Dr Blumer); Arkansas Children's Hospital Research Institute and University of Arkansas for Medical Sciences, Little Rock, Arkansas (Dr Schexnayder, Dr James); the University of Mississippi Medical Center, Jackson, Mississippi (Dr Adcock); Akron Children's Hospital, Akron, Ohio (Dr Reed); and Wyeth Research, Collegeville, Pennsylvania (Dr Paul).
Address for reprints: Gregory L. Kearns, PharmD, PhD, Division of Pediatric Pharmacology and Medical Toxicology, The Children's Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108; e-mail: gkearns{at}cmh.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Pharmacokinetics • children • pantoprazole • safety
The prevalence of GERD in children appears to be increasing. While 25% to 40% of children with GERD will have spontaneous resolution of symptoms, many will require continued medical or surgical management.2-4 Thus, pediatric GERD is a common and significant problem for pediatric patients and their families.
Proton pump inhibitors (PPIs) have become the treatment of choice for GERD for both adults and children. The degree of gastric acid suppression is well correlated with systemic drug exposure reflected by the area under the plasma concentration-time curve (AUC). Thus, the selection of a PPI dose regimen that is associated with clinical efficacy is predicated on providing a proper extent of systemic exposure.5,6 The recommended pantoprazole dose for adults is 40 mg daily for both acute healing of erosive esophagitis and the maintenance of healing. The 20-mg dose is also available for adults.
The doses used in this pharmacokinetic (PK) study were chosen to provide a systemic exposure in children that, based on developmental expression of CYP2C197 and anticipated age-associated changes in body weight, would be predicted to produce systemic exposures that were dimensionally similar to those in adults receiving therapeutic doses of the drug.
In contrast to pantoprazole, the PK of omeprazole and lansoprazole have been well characterized in children older than 2 years of age with acid-related diseases. Available PK data for omeprazole,8 pantoprazole,9 and lansoprazole10 suggest a similarity between adult and pediatric data that supports the use of exposure-response correlates established for adults to guide the dosing of PPIs in pediatric patients requiring acid-suppression therapy.6
The PK of pantoprazole have been characterized extensively in adult subjects but not in pediatric patients. The linear and predictable PK and pharmacodynamic behavior of pantoprazole, as well as its lack of drug-drug interactions and availability as both an oral and parenteral formulation, would appear to make pantoprazole suitable for the treatment of acid-related disorders in children.11-14 The objectives of this study were to determine the PK and tolerability of a single dose of either oral or intravenous pantoprazole in pediatric patients ages 2 to 16 years. This report summarizes data from 2 different clinical trials and provides information with regard to the impact of development and relevant pharmacogenetics on pantoprazole dosing in pediatric patients.
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MATERIALS AND METHODS |
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7 years of age before or at the time of enrollment and before the initiation of any study-related procedure. The identity of each patient was kept confidential in accordance with applicable regulations governing protected health information. Two separate studies of pantoprazole PK were conducted in pediatric patient cohorts (see the following description) to assess the influence of development (ie, age) on the disposition of the drug after both oral and IV administration. All studies had consistent criteria for enrollment and safety monitoring, which are described below.
Subjects were excluded from participation for any of the following reasons: a confirmed history of gastrointestinal (GI) malignancy, organ transplant, renal or hepatic disease or dysfunction, cystic fibrosis, or unstable hemodynamics; having received GI surgery or any surgery that would interfere with metabolism or function of the GI tract, abnormalities in extracellular volume or composition, significant fluid shifts or ascites, active cardiac arrhythmia, or ophthalmologic disorders; abnormal laboratory values of aspartate aminotransferase (AST)/serum glutamicoxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) values 3 times the age-specific upper limit of normal (ULN), total bilirubin >2.0 mg/dL, alkaline phosphataste 5 times the age-specific ULN, or serum creatinine >3 times the age-specific ULN; know hypersensitivity to a PPI, including pantoprazole; a positive serum and urine beta–human chorionic gonadotropin (β-HCG) pregnancy test result; a recent history of alcohol or drug abuse; use of prescription or over-the-counter medications; any known infection with hepatitis B, C, or human immunodeficiency virus (HIV); or participation in a similar investigational study within 30 days of enrollment.
At screening (which could occur within 21 days prior to administration of study drug), each subject underwent a complete clinical evaluation that included a medical history; physical examination including vital signs, measurement of weight (kg) and height (cm); and a clinical laboratory evaluation including complete blood count, biochemical tests to assess renal and hepatic function, acid-base balance, serum gastrin, and a urinalysis. During the course of the study, routine safety and tolerability were evaluated from the results of reported signs and symptoms, scheduled physical examinations, vital sign measurements, clinical laboratory evaluations (including measurements of serum gastrin), and adverse events (AEs). Specific aspects of the 2 studies are described.
Study 1
This was an open-label, multisite, single-dose, randomized, age-stratified, parallel-group study in male and female children aged 5 to 16 years who could benefit from acid suppression therapy whose weight was between the 5th and 96th percentile range.
Patients participated in the study for up to 22 days, consisting of a 3-week prestudy screening period and a 1-day study period. Two age groups (5-10 years and 11-16 years) of 12 subjects each were studied. Within each age group, subjects were randomly assigned to receive a single oral dose of either one 20-mg half-size tablet or two 20-mg half-size tablets (40 mg) of pantoprazole. In each instance, the pantoprazole was administered after an 8-hour (at least) period of fasting. All doses were given with 90 to 120 mL of tap water (25°C), followed by a 2-hour period of fasting.
Study 2
This was an open-label, multisite, single-dose, randomized, age-stratified, parallel-group study in hospitalized pediatric patients aged 2 to 16 years, inclusive, who had a medical need for acid suppression therapy, had a previously inserted nasogastric (NG) tube (deemed suitable for collection of gastric specimens for pH determination), had an anticipated inpatient stay of at least 24 hours, a body weight the 5th percentile for the patient's age, and an indwelling venous cannula suitable for administration of parenteral drugs. Enrolled patients were stratified into 3 groups (6 per group) according to age: 2 to 4 years, 5 to 10 years, and 11 to 16 years. In the 5- to 10-year-old group, at least 2 patients younger than 8 years were planned for enrollment. In the 11- to 16-year-old group, at least 2 patients younger than 14 years were planned for enrollment. All patients received a single pantoprazole dose (0.8 or 1.6 mg/kg), which was infused during a 15-minute period by syringe pump or other infusion rate–controlling device. The maximum single dose did not exceed 80 mg, and the maximum dose per 24-hour period did not exceed 160 mg. Intravenous pantoprazole sodium was supplied as freeze-dried powder. It was reconstituted with 10 mL of normal saline and then diluted with 5% dextrose, 0.9% sodium chloride, or Lactated Ringer's solution to a final concentration of 0.8 mg/mL before use.
Genotyping
CYP2C19 genotyping was performed in all study subjects. Genomic DNA for polymerase chain reactions (PCR) was isolated from whole blood (Study 1 and 2) with a QIAamp Blood Kit (Qiagen, Chatsworth, California). Polymerase chain reaction–restriction fragment length polymorphic–based (RFLP) and primer extension–based protocols within the Pediatric Pharmacology Research Unit (PPRU) Core Pharmacogenetics Laboratory (SOP Version 4, 02-02-2005; Dr Andrea Gaedigk, Children's Mercy Hospitals and Clinics, Kansas City, Missouri; assay details/conditions and a listing of PCR primers used are available upon request) were adapted or modified from the literature.15-20 Genotyping comprised the allelic variants CYP2C19*2 through *8. Allele nomenclature is according to the cytochrome P450 nomenclature Web page at http://www.cypalleles.ki.se/cyp2c19.htm. Assays were performed in the presence of positive DNA controls previously identified to carry CYP2C19*2, *3, *4, or *5 (no positive DNA controls were available for CYP2C19*6, *7, and *8); a negative control accompanied each assay. CYP2C19*2 through *5 constituted the more common allelic variants and were selected for a first "routine" screening. The remaining set of 3 "rare" alleles was screened thereafter if no other alleles had been found or genotype/genotype discordance was observed.
Venous blood samples (1 mL) were collected to measure concentrations of pantoprazole for PK analysis on study day 1 within 2 hours before pantoprazole administration (ie, baseline or time = 0 observation) and at 0.25, 0.50, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after start of IV infusion; 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 hours after oral administration. Blood samples were obtained via syringe from an indwelling venous catheter that was not used for pantoprazole administration and were placed into glass tubes containing sodium heparin, immediately mixed by inversion and centrifuged (1000 g for 10 minutes at 4°C). Plasma was collected by manual aspiration and immediately stored at –70°C until analysis.
Analysis
Pantoprazole was quantitated from plasma samples by a validated high-performance liquid-chromatography method with ultraviolet detection following a solid phase extraction.21 The assay is linear up to 5.0 mg/L using 0.5 mL of human plasma and had a lower limit of quantification of 0.025 mg/L. Intra- and interassay coefficients of variation were consistently 
10% for plasma pantoprazole concentrations within the range of linearity. Frozen (–70°C) stability (90% of starting value for quality control samples) of pantoprazole was established through a period of 12 months. All study samples were analyzed within 12 months of their collection.
Actual blood collection times were used for the analysis. No subjects were excluded from the PK analysis. The PK values for pantoprazole were estimated by noncompartmental methods.22 The values for peak plasma concentration (Cmax) and time to Cmax (tmax) were taken directly from the observed data. Individual concentration-time profiles were plotted, and the terminal elimination rate constant (
z) was determined as the slope from a log-linear least squares regression of at least 3 points judged (by visual inspection) to be in the apparent terminal phase. The terminal-phase half-life (t
) was calculated by dividing ln2 (0.693) by z. Area under the plasma pantoprazole concentration-time curve (AUCT) was determined by the log-linear trapezoidal rule from time zero to the time of the last observed concentration (CT) at time T. Total AUC was determined as AUCT + CT/z. The apparent total plasma clearance (CL)/F and apparent steady-state volume of distribution (Vz/F) were obtained as dose/AUC and dose/(z x AUC), respectively, and further normalized for body weight.
Mean, standard deviation, and coefficient of variation were calculated for the PK parameters for each age and dose group. Intergroup comparisons were accomplished using a 2-tailed, Student t test with the Bonferroni correction applied as necessary for multiple comparisons. All descriptive statistics were calculated using WinNonlin Professional V 4.01. (Pharsight Corporation, Mountain View, California). The dose-independent parameters (CL and t) were examined in light of values previously reported for children18 and adults23,24 and were examined for associations with age using both linear and log-linear regression analyses. All statistical analyses were accomplished using commercially available software (Microsoft Office Excel 2003, v. 5.1; Microsoft, Redmond, Washington) and assumed a level of significance of 
.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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, AUC corrected for weight-normalized dose (AUCcorr), CL/F for oral and CL for IV, and apparent volume of distribution normalized for weight (VD/F for oral and VD for IV). In contrast, the nonnormalized mean value for pantoprazole Cmax after IV administration (8.04 mg/L) was approximately 2.7-fold greater than observed after oral dosing (2.97 mg/L).
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following oral pantoprazole administration in the CYP2C19 extensive metabolizers (Table IV) were approximately 50% lower (P < .05) than corresponding values in the cohort of CYP2C19 extensive metabolizers receiving the IV dose of the drug (Table III). In contrast, neither the apparent plasma CL nor the VD appeared to differ significantly when compared between CYP2C19 extensive metabolizers who received an oral versus IV dose of pantoprazole.
The small number of study participants that could be genotypically classified as a CYP2C19 poor metabolizer (n = 3) precluded statistical comparison of pantoprazole PK parameters based on phenotype. Nonetheless, review of the individual subject data supports comparability (ie, poor vs extensive metabolizers) for both tmax and Cmax after oral administration. As expected, the dose-normalized AUC values for CYP2C19 poor metabolizers (range, 24.7-62.7 mg•h/L per 1 mg/kg) were approximately 6- to 14-fold higher than the mean value (4.3 mg•h/L per 1 mg/kg) for extensive metabolizers (Table IV). As well, the pantoprazole t in the poor metabolizers (range, 5.4-6.5 hours) was approximately 10-fold greater than the mean value (0.63 hours) observed for extensive metabolizers, and the CL/F (range, 0.02 -.04 L/h/kg) was approximately 10-fold lower (ie, 0.3 L/h/kg in extensive metabolizers).
The potential effect of development on pantoprazole disposition was explored through examination of associations between subject age and z, CL/F, and Vz/F. When all data were examined by both linear and nonlinear regression, no statistically significant associations were apparent. Likewise, when PK parameters from the oral (Study 1) and IV (Study 2) dosing cohorts were independently examined for associations with age, no significant correlations were evident. The apparent independence of age on pantoprazole elimination following IV administration in CYP2C19 extensive metabolizers is illustrated by t (Figure 2). Finally, as reflected by the CL data (Figure 3), significant differences were not observed over an age span ranging from 2 to 16 years.
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Safety Results
In Study 1, pantoprazole was well tolerated. There was 1 mild, non-drug–related treatment-emergent adverse event (TEAE). There were no other laboratory or other safety findings of clinical importance. In Study 2, both doses of IV pantoprazole were well tolerated. Treatment-emergent adverse events were reported for 3 subjects who were in the age group 11 to 16 years. No TEAEs were reported for subjects in the other age groups. All TEAEs were mild in severity and considered to be unrelated to study drug. No discontinuations occurred as a result of an AE. Serious AEs—none considered related to treatment—were reported for 3 subjects after they had completed the study. One patient with a serious AE, who was hospitalized for a closed head injury, died 5 days after completing the study (felt by the investigator to be unrelated to study drug). None of the changes from baseline in laboratory test results, vital signs, and weight were considered to be either clinically significant or study-related as assessed by the investigators. Three subjects withdrew from the study prematurely after receiving study medication. None of the withdrawals were related to AEs.
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DISCUSSION |
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While the large therapeutic index for PPIs in general may afford such a generalized approach to pediatric dosing for omeprazole and lansoprazole, available data for this class of drugs suggests that achieving and maintaining a sufficient degree of systemic exposure (reflected primarily by AUC) is required for clinical efficacy.6 A review27 of previous studies of PPI PK performed in a variety of pediatric populations reflects significant variability in the dose-exposure profile that arises in some instances from a dosing artifact (eg, fixed drug dose given to a study population with widely varying body weights), expected normal variability in the constitutive expression of the enzymes primarily responsible for drug biotransformation (eg, CYP2C19 and CYP3A4), polymorphic expression of specific drug-metabolizing enzymes (eg, CYP2C19), and the potential for age-dependence in PPI disposition.
Within the PPI class, lansoprazole, omeprazole, and pantoprazole are all primarily metabolized by a genetically polymorphic enzyme (CYP2C19) produced by inheritance of 2 recessive variant alleles producing a nonfunctional enzyme. CYP2C19 activity is absent in approximately 3% of whites and 20% of Asians, thereby indicating a poor-metabolizer phenotype.28,29 As recently reviewed by Klotz,30 the activity of CYP2C19 determines the level of systemic drug exposure for most of the PPIs, their pharmacodynamic response, and therapeutic outcome (eg, Helicobacter pylori eradication, healing rates of peptic ulcer disease, and GERD).
In adults, CYP2C19 poor metabolizers have increased pantoprazole AUC and decreased clearance compared to extensive metabolizers.31 The limited pediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolizers having 6- to 10-fold higher AUCT values compared with extensive metabolizers.8,20 As expected, differences were observed for pantoprazole when AUC, t, and CL/F were compared between subjects genotyped as CYP2C19 extensive and poor metabolizers (Table IV).
In a previous study of omeprazole PK conducted in pediatric patients with GERD, the dose-corrected AUC was not significantly different between CYP2C19 extensive metabolizers with 1 versus 2 functional CYP2C19 alleles.8 This finding is in contrast to our data for pantoprazole, where the dose-corrected AUC was significantly less for subjects with 2 versus 1 functional CYP2C19 allele (Figure 4). This apparent disparity may be associated with differences between the 2 drugs with respect to the relative contribution of CYP3A4 to their overall biotransformation6,20 and/or differences in the stereoselective biotransformation of pantoprazole by CYP2C1932 that were not accounted for in the bioanalytical results from the present study.
In addition to the pharmacogenetic findings, assessment of the dose-exposure data from the present study enabled us to draw potentially important inferences about the PK of pantoprazole in pediatrics. An approximate doubling of the Cmax after administration of the 0.8 mg/kg (5.7 ± 2.7 mg/L) and 1.6 mg/kg (10.29 ± 3.7 mg/L) IV pantoprazole dose suggests linearity in PK as previously documented for adults.18,20 In the 21 study participants who received oral pantoprazole and were classified as CYP2C19 extensive metabolizers (Table IV), the dose-normalized AUC (4.29 ± 2.08 mg•h/L per 1 mg/kg dose) was approximately 50% of that observed (8.95 ± 7.03 mg•h/L per 1 mg/kg dose; Table III) in subjects who received an IV pantoprazole dose. While the design of the current study precluded a proper assessment of pantoprazole absolute bioavailability in pediatric patients, this suggested bioavailability of approximately 50% is somewhat lower than the average value (ie, 77%) reported from adults who received enteric-coated pantoprazole tablets.33 Finally, we cannot identify a PK rationale to explain the apparent difference for the tmax for pantoprazole following an IV dose of 0.8 mg/kg (0.41 ± 13 hours) versus 1.6 (0.27 ± 0.03 hours) mg/kg. We speculate that this difference would not be of pharmacodynamic significance, and based on the method used to determine tmax (ie, observation), was likely attributable to sampling artifact associated with variance between desired and actual postdose sampling times.
To date, studies of PPIs conducted in pediatric populations have not been able to demonstrate a statistically significant correlation between age and PK parameters.6-10,34 A similar conclusion was obtained from the current data when the PK parameters for pantoprazole (including z, which is not influenced by absorption) from CYP2C19 extensive metabolizers were examined in association with age. The apparent age-independence of pantoprazole PK is further illustrated by similarity in pantoprazole plasma CL after IV administration in children ranging in age from 2 to 16 years and data generated from healthy adults (data on file, Byk-Gulden (Altanta) Protocol No. FHP003 and FHP027E) (Figure 3). Thus, as reflected by the data from the current study, the variability in pantoprazole CL (and by inference, the therapeutic dose requirement) between patients ranging in age from 2 to 16 years appears to be more a function of CYP2C19 genotype than of developmental differences in CYP2C19 activity. Finally, given the potential for developmental differences in CYP2C19 activity in neonates and young infants,35 it is possible that an age dependence of pantoprazole disposition could be observed during the first 2 years of life. Accordingly, determination of an age-appropriate dose for the drug in neonates and young infants will first require characterization of its disposition in these populations.
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CONCLUSION |
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ACKNOWLEDGEMENTS |
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Financial disclosure: The clinical studies, which served as the basis for this manuscript, were supported by research contracts provided by Wyeth to the participating clinical institutions. As well, partial salary and infrastructure support were provided to several of the coauthors (Drs Kearns, Blumer, James, and Reed) through the Pediatric Pharmacology Research Unit (PPRU) Network grants funded by the National Institute of Child Health and Human Development. Finally, several of the investigators (Drs Kearns, Blumer, and James) previously served Wyeth in the capacity of paid consultants in the field of pediatric clinical pharmacology.
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REFERENCES |
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