Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and are the therapy of choice for the treatment of gastroesophageal reflux disease (GERD) in adults (1). High rates of GERD symptom relief and healing of esophagitis have also been observed with PPI therapy in children and adolescents (2–9). There is, however, a distinct scarcity of data regarding the use of such therapy in children, particularly in infants (ie, up to 2 years) with GERD for whom nonpharmacological approaches have failed to control symptoms (10). The importance of effective treatment of GERD in this population should not be underestimated because infants with GERD may experience more serious problems as a consequence of their symptoms, such as failure to thrive and respiratory disorders (11,12).
Esomeprazole is a potent PPI and has recently been approved in the United States and in several European Union countries for the treatment of GERD in patients 12 to 17 years old. Among the PPIs, esomeprazole has shown high pharmacodynamic efficacy for sustained suppression of gastric acid secretion in adults (13–15), although limited data exist on the use of esomeprazole specifically in an infant population. The aim of this study was to evaluate the pharmacokinetics and acid-suppressive effects of different dosages of esomeprazole in infants with symptoms of GERD. The safety of esomeprazole and its effect on symptom severity in this population were also assessed.
PATIENTS AND METHODS
This was a randomized, single-blind, parallel-group study (AstraZeneca study code: SH-NEC-0001) performed at a single medical center (Women's and Children's Hospital, North Adelaide, Australia). The study was undertaken in accordance with the Declaration of Helsinki and codes of good clinical practice. Ethical approval of the study protocol was obtained from the Human Research Ethics and Drug Therapeutics Committees of the Women's and Children's Hospital, North Adelaide. Written informed consent was obtained from each infant's parent or guardian before study commencement.
Infants 1 to 24 months old with symptoms of GERD, who had not responded to nonpharmacological approaches (feed thickeners, antacids, postural changes) if they were 12 months old or younger, were eligible for inclusion. Randomization into the trial was dependent on the diagnosis being associated with significant distal esophageal acid exposure during baseline 24-hour dual pH monitoring (intraesophageal pH <4 for ≥5% of the time) (16). The ability to ingest semisolid food, for infants 3 months old or older, was a further inclusion criterion. Exclusion criteria were as follows: any current or previous clinically significant illness that may interfere with study procedures or with the metabolism of esomeprazole, or that may jeopardize infant safety; receipt of any experimental drug or device in the 8-week period before screening; history of surgical resection of the esophagus, stomach, duodenum, or jejunum; and congenital drug addiction. Use of any pharmacological antireflux therapy up to 24 hours before, or any PPI up to ≤72 hours before, the first dose of study medication was not permitted. Concomitant therapy with anticholinergics, antineoplastic agents, H2-receptor antagonists, sucralfate, bismuth-containing compounds, methylxanthines, promotility drugs, macrolide antibiotics, or barbiturates was not permitted. Known hypersensitivity to esomeprazole, substituted benzimidazoles, or any constituents of the esomeprazole formulation also precluded infants from the study.
Eligible infants were randomized (1:1, according to a computer-generated randomization list provided by the study sponsor) to receive 1 week (7 or 8 days) of treatment with oral esomeprazole 0.25 mg/kg or 1 mg/kg once daily in the morning. Dosages were based on previous clinical experience with omeprazole in children (17) and by taking into account the differences between first-pass metabolism of esomeprazole and omeprazole. Study medication was administered by the parent or guardian for infants 3 months old or older and by study personnel for infants youngerthan 3 months (on day 7/8, esomeprazole was administered at the clinic under the supervision of study personnel). For the purposes of oral administration, the corresponding dose content of identical capsules containing esomeprazole pellets (1.5, 2.5, 5, or 10 mg) was dispersed in approximately 1 teaspoonful of applesauce (for infants 3 months old or older) or emptied into a funnel pan and administered through a specially designed adapter (for infants younger than 3 months). Individual doses were based on infant weight at the prestudy assessment, and a table of doses was used to choose an appropriate combination of capsules. The actual administered dose was not to deviate by more than 30% from the calculated dose.
Additional medication considered necessary for the infant's safety and well-being could be administered at the discretion of the investigator. Commercially available products (eg, Mylanta, Johnson & Johnson-Merck, Fort Washington, PA, or equivalent) could be used for the treatment of gastrointestinal symptoms before the start of treatment but not within 1 hour before first administration of the study drug or during the pH study period.
Compliance with study medication was assessed by measuring the amount of drug used by each infant by counting capsules in returned bottles. Dosing time and any vomiting or inadequate intake of drug were recorded in symptom assessment diaries.
Assessment of Intragastric and Intraesophageal Acidity
The main pharmacodynamic variable was the percentage of time with intragastric pH >4 during 24-hour dual pH monitoring after 1 week of treatment with esomeprazole. Time with intraesophageal pH <4, the overall number of acid reflux episodes, and the number of acid reflux episodes lasting longer than 5 minutes were also evaluated. An acid reflux episode was defined as intraesophageal pH <4 lasting longer than 5 seconds, or, if pH was already <4, reflux constituted a further drop in pH of 1 unit or more, lasting longer than 5 seconds. pH monitoring was performed with a dual pH probe (24 ME multichannel probe, Medtronic Digitrapper Mark III with 1 Hz acquisition rate), with infants fasting for ≥3 hours before intubation. The pH probe was positioned with the esophageal sensor 3 cm above the lower esophageal sphincter. Distance from the nostrils to the lower esophageal sphincter was estimated by use of the established relationship between body length and sphincter position (18). Infants were permitted to go home after the sensor position was confirmed by radiography.
The following pharmacokinetic variables were determined: area under the plasma concentration-time curve (AUC) during the 24-hour dosing interval (AUCτ), AUC from time zero to the last quantifiable concentration (AUC0–t), observed maximum plasma concentration at steady state (CSSmax), time to reach CSSmax (tmax), and plasma terminal half-life (t1/2). AUC was determined by use of the log-linear trapezoidal method; the residual area after the last data point was calculated as Clast/λz, where Clast is the concentration at the last measurable data point and λz is the terminal slope of the log plasma concentration–time profile. t1/2 was calculated as ln2/λz. For a pharmacokinetic variable to be reported, the infant was required to have more than 1 sample above the lower limit of quantification (5 nmol/L) and samples taken for at least 2 hours after dosing. The AUCτ was reported only if <40% of the total AUC was extrapolated. To calculate AUCτ and t1/2, at least 3 samples were required during the declining phase.
Blood samples (0.5 mL) for pharmacokinetic analysis were collected before dosing (within 30 min) and on the last dosing day at 0.5, 1, 1.5, 2, 3, 4, and 6 hours after dosing for infants 3 months old or older and at 1, 2, 3, 4, and 6 hours after dosing for infants younger than 3 months. Plasma concentrations of esomeprazole were determined by reverse-phase liquid chromatography and mass spectrometry, according to the method described by Zhao et al (19).
Assessment of Symptoms
From 2 days before the start of treatment until the end of the treatment period, symptomatic episodes were evaluated by the parent or guardian using a nonvalidated GERD symptom assessment chart (12,20) broadly based on the Infant Gastroesophageal Reflux Questionnaire by Orenstein (21). The chart allowed for recording of the frequency of vomiting, apnea, choking, and behavioral changes (ie, irritability/fussing, back arching, grimacing, gagging). Staff responsible for the routine care of the infant and/or the infant's parents completed the chart whenever these events were observed. Symptoms were scored from 0 (no symptoms) to 3 (severe symptoms; ie, daily reoccurrence of the symptom type).
Safety assessments included adverse events, laboratory measurements, and a general physical examination. Adverse events were reported spontaneously by the parent or guardian and/or in response to an open question as to whether the child had any health problems during the study. Symptoms such as vomiting, crying, gagging, apnea, wheezing, nocturnal cough, vomiting blood, and weight issues were recorded as adverse events only if they were not consistent with the infant's usual symptoms. Causality was assessed by the investigator for serious adverse events only. Routine laboratory safety measurements were assessed at the prestudy visit and before dosing on day 7/8. A general physical examination of each infant, including weight, height, head circumference, pulse, and breathing rate, was performed before entry and at the conclusion of the study.
To provide data sufficient to describe the pharmacodynamic effect and pharmacokinetic profile of esomeprazole in the infant GERD population, the aim was to complete the study with approximately 30 infants whose conditions were evaluable for the pharmacokinetic analysis, of whom at least 24 infants (12 per treatment arm) had to be younger than 12 months old, including at least 2 infants between 1 and 3 months old. Analysis of pharmacodynamic and pharmacokinetic variables was performed by analysis of variance with treatment as a fixed factor for the intention-to-treat population (all of the randomized infants who received 1 dose or more of esomeprazole and for whom postdose data were available). Changes from baseline in the percentage of time with intragastric pH >4 and intraesophageal pH <4 for each treatment were analyzed by use of a paired t test. Pharmacokinetic data are presented as geometric means and medians, and as arithmetic means, inasmuch as some infants had 1 or more plasma concentrations below and/or slightly above the lower limit of quantification that resulted in low and uncertain estimates of exposures, which, to a large extent, affected the geometric mean estimations. The safety population included all infants who received 1 dose or more of esomeprazole and for whom postdose data were available.
The first patient was enrolled on June 6, 2002, and the last patient completed the study on March 23, 2005. In all, 107 infants were enrolled in the study, of whom 50 infants were randomized to receive study treatment (26 in the esomeprazole 0.25 mg/kg group and 24 in the esomeprazole 1 mg/kg group). The main reason the remaining infants were not randomized was lack of significant distal esophageal acid exposure (intraesophageal pH <4 for ≥5% of time) during baseline 24-hour dual pH monitoring. Forty-three infants (86%) were 12 months old or younger, with 9 younger than 3 months. Baseline demographic and clinical characteristics were comparable for the 2 treatment groups (Table 1).
Forty-five infants completed the study (23 in the esome-prazole 0.25 mg/kg group and 22 in the esomeprazole 1 mg/kg group). Of the infants in the esomeprazole 0.25 mg/kg treatment arm, treatment was discontinued in 2 because of withdrawal of parental consent, and 1 infant was withdrawn because of an adverse event (extreme irritability). In the esomeprazole 1 mg/kg treatment arm, treatment was discontinued in 2 infants because of withdrawal of parental consent.
Intragastric and Intraesophageal Acidity
At baseline, the mean percentage of time with intragastric pH >4 was 30.5% (equivalent to 7.3 h) and 28.6% (6.9 h), respectively, in the esomeprazole 0.25 mg/kg and 1 mg/kg groups. After 1 week of treatment, the mean percentage of time with intragastric pH >4 was significantly higher (P < 0.001) with esomeprazole 1 mg/kg (69.3% [16.6 h]; 95% confidence interval [CI]: 60.7%–77.8%) compared with esomeprazole 0.25 mg/kg (47.9% [11.5 h]; 95% CI: 39.4%–56.5%) (Fig. 1). The corresponding mean increases from baseline were 40.6% and 14.0%, respectively (both P < 0.001 vs baseline).
The mean percentage of time with intraesophageal pH below 4 at baseline was 11.6% (equivalent to 2.8 h) and 12.5% (3.0 h), respectively, in the esomeprazole 0.25 mg/kg and 1 mg/kg groups. After 1 week of treatment, mean percentage of time with intraesophageal pH below 4 was lower with esomeprazole 1 mg/kg than with esomeprazole 0.25 mg/kg (5.5% [1.3 h] and 8.4% [2.0 h], respectively, P = 0.06) (Fig. 2). This translated into mean absolute reductions from baseline of 6.7% and 3.5% (P < 0.001 and P < 0.05, respectively). In parallel, the number of acid reflux episodes longer than 5 minutes decreased from a mean of 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. After 1 week oftreatment with esomeprazole 1 mg/kg, the mean total number of acid reflux episodes over 24 hours decreased from 244 at baseline to 176, whereas no decrease was observed in infants receiving esomeprazole 0.25 mg/kg (251 episodes at baseline and 263 on day 7/8).
Figure 3 shows the plasma concentration-time profiles for both doses of esomeprazole. The plasma concentration-time curve for 1 patient in the esomeprazole 1 mg/kg group indicated a markedly higher drug exposure than in the other patients.
The AUC0-t, AUCτ, CSSmax, tmax, and t1/2 of esomeprazole are presented in Table 2. Most infants had fewer than 3 plasma samples collected in the terminal phase. Therefore, AUCτ and t1/2 were calculated for 9 infants only. The geometric means for both AUC0-t and AUCτ were significantly greater in the esomeprazole 1 mg/kg group than in the 0.25 mg/kg group (P = 0.0002 and P = 0.0171, respectively). The CSSmax was reached after a median 2 hours in the esomeprazole 0.25 mg/kg group and after 3 h in the esomeprazole 1 mg/kg group (P = 0.0007). Geometric mean t1/2 was similar in the 2 groups (0.8 h for esomeprazole 0.25 mg/kg and 1.0 h for esomeprazole 1 mg/kg).
Figure 4 shows the effect of age on the pharmacokinetics of esomeprazole by plotting dose-normalized AUC0-t and CSSmax against age. Although data were available only for 6 infants older than 12 months, the magnitude and variability of both AUC0–t and CSSmax seemed to be smaller in these infants than in those younger than 12 months.
Mean symptom scores did not reveal any marked changes in vomiting, choking/gagging, or irritability/crying during 1 week of treatment with esomeprazole 0.25 mg/kg or 1 mg/kg (data not shown).
Safety and Tolerability
Both dosages of esomeprazole were generally well tolerated in this infant population. Adverse events were infrequent (Table 3) and of mild to moderate intensity, and there were no serious adverse events. Three cases of irritability were reported. One 3-month-old infant (with a medical history of colic) in the esomeprazole 0.25 mg/kg group was withdrawn from the trial because of an adverse event (irritability). The event stopped when esomeprazole was withdrawn 4 days later. There were no other clinically important findings with respect to laboratory variables, vital signs, or physical examination findings.
Few data exist on the use of acid-suppressive therapy with PPIs in infants with GERD. The results of the present study show that repeated oral administration of esomeprazole was well tolerated and provided dose-related acid suppression in this specific population. Maintenance of intragastric pH >4 for the greater part of the 24-hour dosing period is a key strategy in the management of GERD in adults (22), and it is reasonable to expect that this objective is equally applicable to infants and children with such symptoms. Overall, the esomeprazole 1 mg/kg dosage achieved a 41% absolute increase in the time with intragastric pH > 4 versus baseline, which was significantly greater than that achieved with esomeprazole 0.25 mg/kg (14% absolute increase). The mean time with intragastric pH > 4 after 1 week of repeated dosing with esomeprazole was similar to that observed in adult patients with GERD. Indeed, Lind et al (23) reported 69.8% and 53.0% of time with intragastric pH > 4 in patients treated with esomeprazole 40 and 20 mg, respectively. Intraesophageal acid exposure also decreased in a dose-dependent manner with esomeprazole therapy in infants with GERD, a finding that was paralleled by a reduction in the number of prolonged acid reflux episodes. Relative to baseline, the mean total number of acid reflux episodes over 24 hours was significantly reduced in the esomeprazole 1 mg/kg group but not in the 0.25 mg/kg group. The reason for the lack of effect in the esomeprazole 0.25 mg/kg group is uncertain. The absolute reduction in intraesophageal acid exposure in the 1 mg/kg group was similar to that reported by Moore et al (17) in a study of infants 3 to 12 months old with GERD who were treated with omeprazole 10 mg (−8.9% with omeprazole vs −6.7% in our study). The significance of our findings regarding intraesophageal pH is limited by the absence of a placebo control group. This potential limitation, however, is offset by the strengths of the study provided by the use of a randomized single-blinded design and the enrollment of 50 infants with symptoms of GERD, a relatively large number of patients for this population. Taken together, these findings indicate that a 1-mg/kg dosage of esomeprazole is more effective than a 0.25-mg/kg dosage for suppressing acid in infants with symptoms of GERD.
After 1 week of treatment with esomeprazole 1 mg/kg, systemic exposure to esomeprazole was similar to that after a 20-mg dose administered repeatedly to adults (23). Mean body weight in the esomeprazole 1 mg/kg treatment group was 8 kg (range, 5.2–18 kg). Infants, therefore, received a lower total dose than 20 mg but a higher dose per kilogram of body weight than adults, indicating that infants have a lower apparent oral clearance but a higher oral clearance per kilogram of body weight than do adults.
Interindividual variability in the exposure (AUC0–t and CSSmax) of esomeprazole was high for both dosages of esomeprazole, particularly in younger infants up to 12 months of age, and was larger than had been observed previously in adults (23). The reasons for the high level of interindividual variability are not fully understood, but several factors may have contributed. First, there were practical and ethical limitations to the number of blood samples that could be taken from infants, so plasma concentration-time curves could not be fully expressed in all of the cases. Second, loss of a proportion of the dose because of spitting/vomiting could theoretically have played a role, although no vomiting was reported to have occurred during the pharmacokinetics assessment day. Third, esomeprazole is mainly metabolized by the CYP3A4 and 2C19 metabolic enzymes (24). The maturation of these enzymes has been reported to start immediately at or before birth, but it is not complete until later in life (25,26). Therefore, different stages of enzyme maturation may be responsible for the higher variability in pharmacokinetic variables in these infants than in adults, and may also explain the higher systemic exposures observed in some children younger than 12 months. However, given that no genotyping for CYP2C19 metabolizer status was performed, it is unknown whether any of the children with higher exposures were CYP2C19 slow metabolizers. Larger than proportional increases in AUC have previously been reported in adults treated with esomeprazole (27). In our study, a larger than proportional increase in AUC was observed, although this was not statistically significant, and no conclusions regarding dose proportionality can be drawn.
Data on the effect of esomeprazole on symptoms of GERD in the infants participating in our trial were inconclusive because there were no obvious changes in vomiting, choking/gagging, and irritability/crying symptom scores during 1 week of treatment. Moore et al (17), in their 2-week crossover trial of omeprazole in irritable infants with GERD, also reported that omeprazole had no effect on irritability despite effective reduction of intraesophageal acid exposure. One reason is that irritability and crying occur commonly in infants and may not necessarily be caused by acid reflux (28). It may also take longer than 1 to 2 weeks for symptoms to improve. Indeed, Alliet et al (29), in their study of 12 infants with GERD who did not respond to cimetidine, noted a marked improvement in symptoms after 6 weeks of treatment with omeprazole 0.5 mg/kg once daily. Additionally, although PPIs alter the acidity of reflux, their effects on the volume and frequency of all reflux events, including weakly acidic reflux between pH 4 and 7 and nonacid reflux, were not examined in this study. In adults, omeprazole has been shown to reduce the frequency of acid reflux but not the frequency of total liquid reflux (as determined by intraluminal impedance techniques) (30). Similar studies in infants have not been published to our knowledge. However, it could be argued that vomiting and the initiation of choking/gagging reflexes arevolume-relatedevents thatmaynotnecessarily be altered by PPI therapy. Finally, the accuracy of the method for symptom scoring may have been compromised by the fact that symptoms were scored if and when they were observed by nursery staff or the parent/guardian, who may have been undertaking other duties and thus could not continuously observe the infant for symptoms.
In our study, repeated daily oral dosing with esome-prazole 0.25 mg/kg and 1 mg/kg was well tolerated. There were no severe or serious adverse events, and esomepra-zole was discontinued because of an adverse event (irritability) in only 1 patient. However, in the absence of a placebo control group and because of the inability of infants to objectively communicate adverse events, it is possible that adverse events may have been underreported (or indeed overreported) by investigators and parents/ guardians.
In conclusion, repeated oral administration of esomeprazole was well tolerated in infants 1 to 24 months old with symptoms of GERD. Esomeprazole provided dose-related acid suppression and decreased esophageal acid exposure, despite marked interindividual variability in pharmacokinetic parameters. An esomeprazole dosage of 1 mg/kg provided the most effective acid suppression, normalizing esophageal acid exposure in this group of patients.
The authors thank the patients and their parents or guardians for their participation in the study, and our colleagues who have worked on and supported this project over several years: Dr Paul Hammond, Dr David Moore, Dr Richard Couper, Mrs Joanna French, Mrs Sue Oliveri, Mrs Michelle Gerace, and Mrs Judy Webster. We also thank Claire Byrne, Jo Dalton, and Steve Winter from Wolters Kluwer Health, who provided medical writing support funded by AstraZeneca.
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