Gastroesophageal reflux (GER) has been defined as the passage of gastric contents into the esophagus with or without regurgitation and vomiting (1). Physiological GER is a normal process that is prevalent in infant and slightly older children and resolves without sequelae (2–7). Children who have chronic reflux may exhibit clinical manifestations such as irritability, vomiting, and weight loss. Chronic GER that is pathological and leads to symptoms or complications, such as esophagitis, stricture, Barrett esophagus, and a variety of extraesophageal sequelae, is referred to as gastroesophageal reflux disease (GERD) (1,8). Without proper management, children with GERD may continue to experience complications as adults (9,10).
Pharmacological intervention is often necessary to relieve symptoms associated with reflux and GERD, promote healing of esophageal tissue, and prevent or manage complications. Proton pump inhibitors are widely considered to be effective pharmacological agents available for the suppression of gastric acid secretion and are at the core of treatment in adults with GER and GERD (1,11). The available proton pump inhibitors have a similar mode of action through inactivation of parietal cell hydrogen-potassium adenosine triphosphatase in the secretory membrane. All of the proton pump inhibitors suppress basal and stimulated secretion of a gastric acid (12). Several published studies have demonstrated that proton pump inhibitor therapy is an effective and well-tolerated treatment of erosive esophagitis and GERD in children (13–19). Proton pump inhibitors approved in North America and Europe for use in children 1 year old or older include omeprazole and esomeprazole, and lansoprazole (the latter in North America only). Pantoprazole and rabeprazole have been approved in the United States for use in children 5 and 12 years old or older, respectively. (1,20,21).
Like other agents in its class, rabeprazole produces rapid and effective suppression of gastric acid secretion in adults that is maintained after daily administration. Compared with placebo, a single 20-mg dose of rabeprazole reduced 24-hour intragastric acidity in healthy subjects by 66%, whereas administration of 20 mg for 8 consecutive days reduced intragastric acidity by 82% (22). Comparative studies have demonstrated that rabeprazole possesses greater antisecretory potency relative to equivalent milligram doses of esomeprazole, lansoprazole, omeprazole, and pantoprazole (23–26). Rabeprazole has been shown to effectively heal esophageal erosions, relieve symptoms attributable to reflux disease and GERD, and prevent relapse in adults with erosive esophagitis during placebo-controlled, double-blind, and open-label studies (27).
The pharmacokinetics of rabeprazole was investigated previously in adults (28,29). Maximum concentrations (Cmax) in plasma were variable and observed 3 to 5 hours after dosing. The Cmax and area under the concentration-time curve (AUC) in plasma increased in a linear manner when 10 to 80 mg was administered. The absolute oral bioavailability is approximately 52%. No significant accumulation in plasma is apparent after once-daily administration, which is consistent with an apparent short half-life of approximately 1 hour. According to the US prescribing information, concomitant administration of rabeprazole as an oral tablet with a high-fat meal may delay absorption up to 4 hours or longer; however, plasma Cmax and AUC values are not significantly altered. Thus, rabeprazole may be taken irrespective of the timing of meals. The pharmacokinetic properties of rabeprazole given as an enteric-coated tablet in children ages 12 to 16 years were similar to adults (30). Single and once-daily administration of 10 and 20 mg were well tolerated by these adolescent patients.
All of the available proton pump inhibitors, including esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, undergo extensive biotransformation (31–33). This may result in the loss of a significant fraction of an oral dose (range 10%–75%) through first-pass metabolism from hepatic and hepatic-independent processes, and clearance that is independent of renal function. Three primary metabolic pathways have been identified for this class of drugs: hepatic oxidative biotransformation by cytochrome P450 (CYP) 2C19 and 3A4 and reductive biotransformation of the sulfoxide moiety to a thioether by non–CYP-dependent processes, either as a nonenzymatic process or as a cytosolic or intestinal flora reductase–dependent process. Currently, an understanding of the mechanism of this reduction in the biotransformation of proton pump inhibitors in general and biotransformation of rabeprazole in particular is unclear. Rabeprazole is metabolized primarily to a thioether, which is further biotransformed to a desmethyl thioether and then a thioether carboxylic acid. Rabeprazole is also metabolized by CYP2C19 and CYP3A4 to form desmethyl and sulfone metabolites, respectively (29,34,35).
The present study is the first systematic assessment of rabeprazole in children 1 to 11 years old. The primary objective was to characterize the pharmacokinetic profile of rabeprazole after the first administered dose and after once-daily administration for 5 days as enteric-coated beads in an aqueous oral suspension to children with GERD. Subjective evaluations included Clinical Global Impression for Severity of Illness (CGI-S) and Change (CGI-C) subscales to determine the severity of the GERD condition and to evaluate effectiveness of rabeprazole, respectively. Palatability data were collected to evaluate the degree of taste acceptability and ease of swallowing the vehicle-suspended bead formulation. In addition, the safety profile of single and repeated doses of rabeprazole was characterized. The information gathered from the present study has been used to identify the rabeprazole doses being investigated during an ongoing definitive safety and efficacy study in the same age group.
PATIENTS AND METHODS
Male and female patients with GERD between the ages of 1 and 11 years 364 days and a minimum body weight of 10 kg were eligible for study enrollment. The patients were stratified by age to ensure that at least 2 patients 1 to 3 years, 3 to 8 years, and 8 to 11 years 364 days old were assigned to each of the 3 dose groups. The diagnosis of GERD was confirmed via endoscopic examination performed before the initiation of an ongoing treatment of the patient's GERD, or from a diagnosis made before enrollment in the study. Patients who were being treated with a proton pump inhibitor, H2 blockers, or antacids were eligible for enrollment if they discontinued these agents for least 3 days before rabeprazole dosing (except for cimetidine, which was to be discontinued for at least 7 days before dosing). Patients with stable asthma/reactive airway disease or cystic fibrosis–dependent GERD symptoms on stable treatment regimens or on stable doses of allergy and attention-deficit/hyperactivity disorder medicines were eligible for enrollment. Use of other medications (with the exception of the occasional use of acetaminophen) was not permitted within 14 days before the first dose of rabeprazole.
Patients were excluded from participation for any of the following reasons: history of or current clinically significant medical illness (eg, cardiac arrhythmias or other cardiac disease, hematological disease, coagulation disorders, lipid abnormalities, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, neurological or psychiatric disease, infection, peptic ulcers, esophageal motility disorders, eosinophilic esophagitis); primary pulmonary or ear, nose, and throat symptoms (eg, bronchospasm, aspiration pneumonia, chronic nasal blockage, cough, stridor, hoarseness, laryngitis, recurrent bronchitis, nocturnal asthma, bronchopulmonary dysplasia not secondary to GERD); uncorrected electrolyte disorders, laboratory values outside the normal age-appropriate range that were deemed clinically significant by the investigator; presence of gastric Helicobacter pylori; and history of sensitivity to proton pump inhibitors. Patients with known chromosome or congenital anomalies of the gastrointestinal tract, heart, or liver were to be excluded unless, in the judgment of the investigator, there was no risk to the patient and if the medical illness was not expected to interfere with the interpretation of the study results.
The number of patients to be enrolled in this study was not based on statistical considerations, but it was of a sufficient size to obtain a reasonable estimate of pharmacokinetic parameters in the subject population. That is, a sample size of 6 completed patients in each dose group was sufficient to ensure that the estimate of the mean pharmacokinetic parameters would fall within 85% to 118% for 20% coefficient of variation (%CV), and 72% to 139% for 40% CV, of the true value with 90% confidence. These estimated intersubject variabilities for rabeprazole Cmax and AUC (ie, 20% and 40%) were based on previously completed studies performed in adults.
This was an open-label, multicenter (14 investigative sites in the United States and Belgium), single- and multiple-dose, phase 1 study that was conducted from March 2008 to September 2009. The study consisted of 2 parts each consisting of 3 phases. The first phase of each part included a screening period during which participating children underwent a complete medical history and physical examination, electrocardiography (ECG) assessment, and routine clinical laboratory examinations (eg, hematology, chemistry, urinalysis) up to 21 days before the first dose of rabeprazole. The second (treatment) phase of parts 1 and 2 consisted of a 5-day dosing regimen with rabeprazole (described below). At the investigator's discretion, patients were treated as outpatients or remained at the investigative sites from the time that the predose sample was collected on day 1 until the last serial pharmacokinetic sample was collected on day 5. The final, posttreatment phase occurred within 2 weeks after the last dose of rabeprazole and included a physical examination, ECG, and clinical laboratory assessments. Each patient participated in the study for approximately 6 weeks.
Patients enrolled in part 1 of the study received approximately 0.14 mg/kg (using increments of 1 mg) of rabeprazole once daily on days 1 to 5. This dose is comparable with the lowest effective adult dose (10 mg of rabeprazole) specified in the product label (on a per-kilogram body weight basis, assuming a 70-kg adult). Patients were enrolled in part 2 of the study after review of the safety and pharmacokinetic data collected during part 1. During part 2, patients were randomly assigned to receive approximately 0.5 or 1 mg/kg (using increments of 1 mg) of rabeprazole once daily on days 1 to 5. These doses were expected to produce plasma AUC values of approximately 400 and 800 ng/h/mL, respectively, which are levels of exposure within the range observed in adults who were administered 10- and 20-mg oral doses of rabeprazole, respectively (28,29). Patient assignment to either of 2 dose levels in part 2 of the study was performed using a computer-generated randomization schedule that was balanced, included randomly permuted blocks, and stratified patients by age.
Rabeprazole was supplied as 470-μm enteric-coated, orange-colored, granule formulation of the sodium salt in sachets containing either 1 or 5 mg of the drug. A suspension was prepared by combining separate sachets of the microgranules and strawberry-flavored vehicle (0.2 or 1 g of pink granules) and then reconstituted with 10 mL of water. Daily doses of rabeprazole were given in the morning at approximately the same time of day shortly after being prepared and administered by the investigator or designated staff. Each dose of rabeprazole was administered orally to the patients, after an overnight fast, via syringe. Tap water (approximately 2 mL) was used to rinse any residual suspension in the syringe and administered to the patients. A light meal was offered at 30 minutes after dosing and a normal diet was permitted at 1 hour after dosing. Compliance with study-related procedures, including rabeprazole administration, was ensured by the supervision of study site personnel.
The study was conducted in accordance with the provisions of the World Medical Association Declaration of Helsinki and its amendments concerning medical research in humans and in conformance with all of the local laws and regulations. Documentation procedures complied with International Conference of Harmonization guidelines. Study procedures were designed to ensure adherence to Good Clinical Practices and the 21 Code of Federal Regulations. Before screening, written consent was required by the child's parent (both, if available) or guardian. Assent was obtained from children capable of understanding the nature of the study, typically patients 7 years old and older, depending on the institutional policies. Approval for the study was obtained from an independent ethics committee or institutional review board at each participating investigative site.
Blood samples (1 mL each) were collected from an indwelling venous cannula on day 1 (immediately after single oral administration) and on day 5 (after daily administration for 5 consecutive days) before rabeprazole administration (time = 0) and at 1, 2, 4, 6, 8, and 12 hours postdose. The samples were collected into glass tubes containing sodium heparin, inverted for mixing, and then centrifuged at 4°C at 3910g for 5 minutes. The plasma was transferred by manual aspiration into polypropylene storage tubes containing sodium hydroxide (final concentration 0.08 N) and immediately stored at −20°C or lower until analysis.
The concentrations of rabeprazole and the thioether metabolite were simultaneously measured in plasma using a validated liquid chromatography-tandem mass spectrometry system at QPS, LLC (Newark, DE). The samples were spiked with omeprazole (internal standard) and processed by solid-phase extraction. Chromatographic separation was done on a reversed-phase column. Detection was performed by tandem mass spectrometry with Turbo-IonSpray – (Applied Biosystems, Carlsbad, CA) positive ions for rabeprazole, the metabolite, and the internal standard were monitored in multiple reaction-monitoring mode. Before start of the study, the parent drug and metabolite were determined to be stable in human whole blood in the presence of sodium hydroxide at room temperature for at least 1 hour. The time between collecting blood and freezing the plasma samples did not exceed 20 minutes. Furthermore, stability of both analytes in human plasma in the presence of sodium hydroxide was demonstrated under the following conditions: at least 12 hours at room temperature, after 3 freeze-thaw cycles, and after 373 days at −20°C. The plasma samples used for pharmacokinetic assessment and included in the present analyses were stored at −20°C and assayed within this time after their respective collection dates. In addition, stability of analytes in solvent, the autosampler, and processed samples was confirmed. The limits and quantification range of the assay for both rabeprazole and the metabolite were 5 to 1000 ng/mL. All of the calibration curves had coefficients of determination ≥0.9912. The inter- and intraassay variability (expressed as percent coefficient of variation) for rabeprazole and thioether metabolite quality control samples did not exceed 7.6%.
Pharmacokinetic parameters of rabeprazole and the thioether metabolite were estimated using noncompartmental methods (WinNonlin, version 5.2.1, Pharsight Corporation, Mountain View, CA) including maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), AUC from time 0 hours to the time of the last measurable concentration (AUClast), and for the entire 12-hour sampling interval (AUCall). The AUC from 0 hours to infinite time (AUC∞) was calculated as the sum of AUClast + Clast/λz (where Clast is the last measurable concentration and λz is the terminal phase elimination rate constant). Total plasma clearance of rabeprazole following single-dose administration was calculated based on the ratio of dose/AUC∞. The terminal half-life was calculated by the ratio of 0.693/λz. Concentrations below the limit of quantification were treated as 0.
CGI-S, study drug treatment, and study drug palatability were assessed using various scales. The investigator completed the CGI-S on day 1. Possible responses included 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill. The CGI-C and Global Assessment of Effectiveness were completed on day 5. The former required investigators to record how much a patient's GERD symptoms changed compared with the patient's baseline condition, with possible responses including 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Effectiveness of rabeprazole was assessed by the investigator using a 4-point scale (0 = poor, 1 = fair, 2 = good, 3 = excellent) when responding to the question: How effective do you feel the current treatment is at the present time? Palatability (including ease of swallowing) of the vehicle-suspended rabeprazole beads was assessed daily on day 1 through day 5 by the patient's parent using a 4-point scale (0 = poor, 1 = fair, 2 = good, 3 = excellent) when responding to the question: How palatable (including easy to swallow) do you feel the study medication is?
The safety of once-daily administration of rabeprazole was assessed by the recording adverse events throughout the study. In addition, physical examinations, clinical laboratory tests, vital signs, and 12-lead ECG were performed during screening, 1 day before rabeprazole administration, and after discontinuation of treatment.
Twenty-eight patients, predominately white, with endoscopically proven GERD were enrolled in the study (Table 1). Four patients had an ongoing history and 1 patient had a history of asthma. Concomitant medications were used by 18 patients; the most common were treatments for attention-deficit/hyperactivity disorder (3 patients) and asthma (2 patients) and were not likely to substantially influence the pharmacokinetics of rabeprazole. Eight patients received approximately 0.14 mg/kg of rabeprazole during part 1 of the study. During part 2, 11 patients were randomized to receive approximately 0.5 mg/kg of rabeprazole and 9 patients were randomized to receive approximately 1 mg/kg of rabeprazole.
Of the 28 enrolled patients, 27 completed the study. One patient from the 0.5-mg/kg rabeprazole dose group was withdrawn because of an adverse event (viral gastritis) on day 5 after the last rabeprazole dose was given. All 28 patients received rabeprazole once daily for 5 successive days and bioanalysis was performed on plasma samples collected from all of the enrolled patients; however, 3 patients (1 on day 5 from the 0.5-mg/kg dose group; 2 on day 1 from the 1-mg/kg dose group) either spit out or vomited much of the rabeprazole dose. In addition, pharmacokinetic samples from 1 patient collected on day 1 (0.5 mg/kg) were analyzed after being stored in frozen conditions for a time that exceed the interval for which drug stability was demonstrated. The pharmacokinetic results from these 4 profiles were excluded from the present analyses.
The mean plasma concentration-time profiles of rabeprazole following single-dose and once-daily administration of 0.14, 0.5, and 1 mg/kg are presented in Figure 1A. The corresponding pharmacokinetic parameters are presented in Table 2. The plasma AUC and t1/2 values could not be estimated for most patients in the lowest dose group (0.14 mg/kg) because rabeprazole concentrations were below the limit of quantitation (5 ng/mL) shortly after dosing.
Maximum concentrations of rabeprazole in plasma were observed, on average, at 1.52 to 2.43 hours after single-dose and multiple once-daily administration of rabeprazole. The mean plasma Cmax and AUC values increased with increasing dose. The mean t1/2 values ranged from 1.1 to 1.9 hours. The mean plasma rabeprazole CL/F values on day 1 were 513 mL/min (or 25.8 mL · min−1 · kg−1) and 714 mL/min (or 30.8 mL · min−1 · kg−1) for the 0.5- and 1-mg/kg dose groups, respectively.
Plasma rabeprazole concentrations accumulated to a modest degree following repeated administration. On average, the plasma AUCall values were 1.16 to 1.39 times higher on day 5 relative to day 1. These mean accumulation ratios were influenced by outlying values because the median of the ratio values were closer to unity (range 0.97–1.08).
Plasma AUC∞ values that were adjusted for the rabeprazole dose administered are shown as a function of total body weight and age to evaluate the relation between rabeprazole exposure and these demographic variables. A high degree of overlap in the individual AUC∞ values across the horizontal axis of each plot was observed (Fig. 2A).
Thioether Metabolite of Rabeprazole
The mean (SD) plasma concentration-time profiles of thioether metabolite following single-dose and once-daily administration of rabeprazole are presented in Figure 1B. The corresponding plasma pharmacokinetic parameters are presented in Table 3.
Maximum concentrations of the thioether metabolite in plasma were observed, on average, 2.82 to 4.75 hours after single-dose and multiple once-daily administration of rabeprazole. The mean plasma Cmax and AUC values increased with an increase in the rabeprazole dose. Plasma thioether metabolite concentrations were of the same order of magnitude as the parent. The mean t1/2 values ranged from 2.2 to 2.9 hours. The concentrations of the thioether in plasma accumulated to a modest degree following repeated administration. On average, the plasma AUCall values were 1.32 to 1.54 times higher on day 5 relative to day 1.
Individual dose-adjusted plasma AUC values were displayed as a function of total body weight and age to evaluate the relation between metabolite concentrations and these demographic variables. A high degree of overlap in the individual AUC across the horizontal axis of each plot was observed (Fig. 2B).
CGI-S and CGI-C Subscales
Of the 25 patients assessed on day 1 for CGI-S, 16 patients were mildly ill and 9 patients were moderately ill. When assessed during the end-of-study visit or early withdrawal using CGI-C, 4 (14.3%) patients were very much improved; 17 (60.7%) of enrolled patients were much improved; 4 (14.3%) patients each were minimally improved; 2 (7.1%) patients had no change in their condition; and 1 (3.6%) patient was minimally worse.
Global Assessment of Effectiveness
At the end of the study or early withdrawal, the investigator assessed the effectiveness of treatment as poor for 1 (3.6%) patient, fair for 2 (7.1%) patients, good for 15 (53.6%) patients, and excellent for 10 (35.7%) patients.
On day 1, most of the patients' parents found the palatability of the study drug to be good (n = 10) or excellent (n = 9). Palatability of the study drug was rated as fair and poor by 5 and 4 patients' parents, respectively. By the end of the study or early withdrawal, most of the patients' parents found the palatability of the study drug to be excellent (n = 12) or good (n = 11); 2 of them found the palatability of the study drug to be fair, whereas 3 found it to be poor.
No deaths were reported during the present study. One patient (0.5 mg/kg rabeprazole) was withdrawn from the study because of a serious adverse event after receiving the last dose of rabeprazole on day 5. She was diagnosed as having moderate viral gastritis on day 4, severe intestinal volvulus on day 7 (both considered to be doubtfully related to the study drug), and moderate hepatitis on day 19 (considered not to be related to the study drug). No clinically meaningful differences in treatment-emergent adverse events were observed among the 3 dose groups. Twenty-one (75%) patients reported at least 1 treatment-emergent adverse event each: 5 (62.5%) patients receiving 0.14 mg/kg rabeprazole, 9 (81.8%) patients receiving 0.5 mg/kg rabeprazole, and 7 (77.8%) patients receiving 1 mg/kg rabeprazole.
Most of the treatment-emergent adverse events were mild in severity and considered not to be related to the study drug (Table 4). The exceptions were as follows: One patient (1 mg/kg rabeprazole) experienced a mild elevation of serum gastrin levels reported as probably related to the study drug. The patient's gastrin concentrations on days 1, 19, and 54 (an unscheduled visit) were 223, 1015, and 92 ng/L, respectively (normal range 25–111 ng/L). Two additional patients exhibited gastrin concentrations that exceeded the upper limit of normal (0.14 mg/kg rabeprazole: 163 and 115 ng/L on days 1 and 18, respectively; 0.5 mg/kg rabeprazole: 190 ng/L on day 19). These observations were reported by the investigator as mild and not related and doubtfully related, respectively, to rabeprazole administration. Three patients reported the following events as possibly related to the study drug: mild increase in blood uric acid and decrease in hemoglobin (0.14 mg/kg rabeprazole), mild heart murmur (1 mg/kg rabeprazole), and mild diarrhea (1 mg/kg rabeprazole).
Five moderate and 1 severe treatment-emergent adverse events, not related or doubtfully related to rabeprazole, were reported in 3 patients. One patient (0.14 mg/kg rabeprazole) experienced moderate dizziness and 2 episodes of moderate headache. Another patient (1 mg/kg rabeprazole) also experienced moderate headache. A third patient (0.5 mg/kg rabeprazole) experienced moderate viral gastritis, a severe volvulus, and moderate hepatitis (described above).
Values above or below the normal reference ranges for clinical laboratory parameters, vital signs, and ECG parameters were reported during the study, but none were considered clinically significant. No clinically meaningful dose-related or time-related trends were observed in these variables. The mean serum gastrin concentrations at baseline (ie, predose on day 1) were 61.8 ng/L (n = 8), 57.4 ng/L (n = 8), and 82.6 ng/L (n = 5) for the 0.14-, 0.5-, and 1.0-mg/kg dose groups, respectively. The mean concentrations in samples collected at the end of the study were 58.3 ng/L (n = 7), 97.3 ng/L (n = 6), and 216.8 ng/L (n = 6), respectively. None of the physical examination abnormalities observed was considered to be clinically significant, with the exception of 1 patient with a heart murmur at screening. This patient had a history of systolic murmur secondary to ventricular septal defect.
The disposition of drugs in children can be different from that in adults. Developmental changes in the biotransformation, distribution, and hepatic and renal clearance of drugs have been established (36). The pharmacokinetics, safety, and efficacy of rabeprazole were previously characterized in adolescent patients 12 to 16 years old with GERD treated with single-dose and once-daily administration of 10- and 20-mg enteric-coated rabeprazole tablets (30). The plasma clearance of rabeprazole and terminal half-life values were within the ranges observed in adults, leading the authors to conclude that dose adjustment in patients within the ages of those enrolled is not warranted. The dose recommended in the US package insert is fixed (ie, 20 mg of rabeprazole) for patients 12 to 16 years old. In addition, the rabeprazole regimens tested were well tolerated.
The patients enrolled in the present study received rabeprazole as an aqueous oral suspension. Rabeprazole enteric-coated microgranules and vehicle were mixed and then reconstituted with water before dosing. The oral bioavailability of this formulation, relative to the 10-mg enteric-coated tablet, was assessed during a previously completed, unpublished, open-label, 2-period, 2-sequence, crossover study in healthy adults (study E3810-A001-015). Results available from 16 subjects indicated that rabeprazole was readily absorbed when given as the suspension (mean Tmax, 2.4 hours) and the tablet (mean Tmax, 3.8 hours). The mean plasma Cmax and AUC values produced following administration of the rabeprazole suspension were approximately 174 ng/mL and 341 ng/h/mL, respectively, which were 65% and 91%, respectively, of those obtained with the tablet. The mean apparent terminal half-life of rabeprazole was approximately 0.9 hours for both formulations. Approximately 73% of the adult subjects rated the overall acceptance as of the suspension formulation as “like” or “like very much.”
The present study is the first systematic assessment of rabeprazole pharmacokinetics, subjective evaluations of efficacy, and safety in children 1 to 11 years old with GERD. Rabeprazole was rapidly absorbed after oral administration of the suspended microgranules to children enrolled in the present study. The mean tmax values ranged from 1.5 to 2.4 hours across the dose groups, which is comparable to the mean tmax value observed in adults administered 10 mg as the same rabeprazole formulation (mean value 2.4 hours from unpublished phase study E3810-A001-015), although shorter than the range of values previously reported when given to adults and adolecents as a tablet (range of mean values 2.9–5.1) (27–29). Dose proportionality was not formally assessed; however, mean plasma AUC values for rabeprazole and the thioether metabolite on days 1 and 5 increased in a dose-dependent manner for the 0.5- and 1.0-mg/kg regimens. A similar observation was made for mean plasma Cmax values, with exception of the unexpectedly similar values on day 1 for the parent. The latter observation is likely attributable to the relatively high variability in Cmax values and small number of patients in each dose group. Little to no accumulation was observed in the concentrations of rabeprazole, consistent with its apparent plasma half-life of approximately 1 to 2 hours. The metabolite accumulated modestly (on average 1.3 to 1.5 times), although none was expected given the half-life in plasma of approximately 2 to 3 hours calculated for patients in the present study. The pharmacokinetics were consistent after single and repeated dosing as was evident by the comparable half-life values of the parent and metabolite after single and daily administration.
The results of the present study provide evidence that adjustment of the rabeprazole dose on the basis of age or total body weight in this age group may not be warranted. A high-degree overlap was observed in the plasma AUC values of rabeprazole and thioether metabolite (when corrected for the absolute dose) across the range of age and body weights of the enrolled patients. Additional evidence is provided by the comparable mean apparent rabeprazole clearance from the present study (513 and 714 mL/min following single-dose administration of 0.5 and 1 mg/kg, respectively) relative to previously reported values in healthy adults (550 and 817 mL/min) and adolescents (mean 859 and 639 mL/min, based on reported mean weight-corrected clearance values and total body weights) (30,37,38). The results from the comparison of clearance values across studies should be interpreted cautiously because the estimates are confounded by oral bioavailability from the various rabeprazole formulations.
The mean oral clearance values of rabeprazole expressed per unit of total body weight are higher for the patients from the present study (25.8 and 30.8 mL · min−1 · kg−1 for the 0.5- and 1.0-mg/kg dose groups, respectively) than those reported previously in adults (range 4.37–10.1 mL · min−1 · kg−1) and adolescents (10.1 and 12.6 mL · min−1 · kg−1) (28,29). Thus, approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable therapeutic concentrations in adults.
Absence of developmental dependence between the pharmacokinetics has also been reported for proton pump inhibitors lansoprazole (ages 1–11 years), omeprazole (ages 2–16 years), and pantoprazole (ages 2–16 years) (39–41). The results of a small study in children 1 to 11 years old suggested that the pharmacokinetic properties of esomeprazole were dependent on age (42); however, the apparent dose-dependent disposition of this drug may have confounded the results. The recommended dose schedules for these 4 proton pump inhibitors include drug-specific stratifications of pediatric patients by body weight.
Unlike other proton pump inhibitors, rabeprazole is biotransformed predominately through nonenzymatic processes that do not involve hepatic CYP-mediated reactions. A thioether is a predominant metabolite found in fairly high concentrations, relative to the parent drug, in the plasma of adults and adolescents administered rabeprazole (29,30,43). The results of the present study demonstrate that formation of the thioether is a major pathway through which rabeprazole is metabolized in younger patients as well. It is also notable that the mean apparent plasma half-life values of the metabolite in the pediatric patients were within the range reported previously for older subjects.
The systemic exposure to rabeprazole, reflected by the estimated AUC∞ values on day 1 for the 0.5-mg/kg (mean 346 ng/h/mL) and 1-mg/kg (mean 785 ng/h/mL) dose groups, were close to those targeted (400 and 800 ng/h/mL, respectively). Notably, they are consistent with the exposure reported in adults administered therapeutic doses of 10 and 20 mg (28,29). Thus, it is supportive that the severity of illness appeared to reduce and a majority of pediatric patients were much improved after treatment with rabeprazole in this short-term assessment. A dose response in CGI-C or Global Assessment of Effectiveness was not apparent, which may be attributable to the relatively small number of patients enrolled. The palatability, including taste and ease of swallowing, of the rabeprazole formulation tested during the present study was acceptable for most of the patients. Furthermore, the single and repeated doses of rabeprazole were well tolerated. Most treatment-emergent adverse events were mild in severity, with the most frequently reported being vomiting and cough (n = 3, each 10.7%). Treatment-emergent events that were moderate or severe in nature were considered by the investigator as doubtfully related or not related to rabeprazole.
The present study is the first assessment of rabeprazole pharmacokinetics, subjective evaluations of efficacy, and safety in children 1 to 11 years old with GERD. The plasma rabeprazole concentrations increased in a dose-dependent manner across the doses administered. Little or no accumulation in plasma was observed after once-daily administration, consistent with a half-life of 1 to 2 hours. The apparent absence of an association between individual age and body weight and plasma rabeprazole AUC values, and the similarity in oral clearance values when compared with adults enrolled in previous studies suggest that rabeprazole dose adjustment on the basis of either demographic variable may not be warranted. The main metabolite previously identified in the plasma of adults administered rabeprazole was also present in high concentrations, relative to the parent drug, in pediatric patients.
Subjective evaluations (Global Change subscale and Global Assessment of Effectiveness) by investigators indicated that GERD severity was reduced and the majority of patients were much improved after short-term treatment with rabeprazole. Most of the patients' parents found the palatability of the rabeprazole suspension to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety profile among the 3 treatment groups.
We thank the children and parents for their participation in the present study. The authors also acknowledge the collaboration and commitment of all of the investigators and their staff: Belgium: Drs Etienne Sokal, Yvan Vandenplas, Gigi Veereman, André Vertruyen; United States: Drs Ali Bader, Phyllis Bishop, Jeffrey Blumer, Yoram Elitsur, George Konis, Molly O'Gorman, Janice Sullivan, Jonathan Teitelbaum, and Vasundhara Tolia. We also thank Daksha Desai-Krieger and Tom Verhaeghe for their bioanalytical support and Joe Murphy for assistance with the pharmacokinetic analyses.
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