Gastroesophageal reflux disease (GERD) is a condition of multifactorial etiology resulting in the reflux of gastric contents into the esophagus through the lower esophageal sphincter. GERD is a chronic disease that can persist through adulthood, with symptoms observed in older children and adolescents being similar to those seen in adults (1,2). Younger children generally present with extraesophageal manifestations, regurgitation, and epigastric pain, whereas older children and adolescents typically present with adult-type GERD symptoms of heartburn and regurgitation (1,3,4).
Pharmacologic therapies for GERD include acid-buffering therapies, prokinetics, and suppression of gastric acid by the H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). Since approved in 2002 for treating pediatric patients with GERD in the United States, lansoprazole has established its effectiveness and tolerability in patients ages 1 to 17 years for the short-term treatment of symptomatic GERD and erosive esophagitis (EE) (5). The pediatric use of lansoprazole is supported by evidence from placebo-controlled clinical studies (6–9) in the adult population with supplemental clinical, pharmacokinetic (PK), and pharmacodynamic studies performed in pediatric patients (10,11). The PK profile of lansoprazole 15 and 30 mg administered for 5 days in adolescents 12 to 17 years of age with GERD was similar to that observed in studies of healthy adults (10).
The PPI dexlansoprazole is the R-enantiomer of lansoprazole. Dexlansoprazole MR is a modified-release formulation of dexlansoprazole that uses an innovative dual delayed release (DDR) delivery system. The DDR formulation results in a dexlansoprazole plasma concentration time profile with 2 distinct peaks: the first peak occurs 1 to 2 hours after administration, followed by a second peak within 4 to 5 hours (12). Compared to a conventional delayed-release formulation, the DDR formulation results in a higher dexlansoprazole area under the plasma concentration time curve (AUC) without a commensurate increase in mean peak plasma concentration (Cmax) (12).
Dexlansoprazole MR was approved and introduced to the US marketplace in 2009 for the indications of healing all grades of EE, maintenance of healed EE, and treatment of symptomatic nonerosive GERD in adults (13). Dexlansoprazole MR has been studied in more than 5000 patients older than 18 years in completed phase 1 and phase 3 studies (14). The safety profile of dexlansoprazole MR compared with both lansoprazole and placebo in the phase 3 trials was similar (14). There have been no findings in the clinical trials conducted with dexlansoprazole MR in adults that would suggest any potential safety concerns in the pediatric population.
Although the PK and safety profiles of dexlansoprazole MR have been extensively studied in adults, dexlansoprazole MR has not been studied in patients younger than 18 years. The 30- and 60-mg doses were selected because these doses were studied in phase 3 studies in adults. The primary objectives of this study were to assess the PK and safety profiles of dexlansoprazole MR 30- or 60-mg capsules following daily administration in adolescent patients 12 to 17 years of age with symptomatic GERD.
PATIENTS AND METHODS
Male and female adolescents (12–17 years of age and body weight ≥30 kg), with physician-documented histories of GERD symptoms for at least 2 months before the screening period, were eligible for enrollment. Dosing of dexlansoprazole MR was not weight based in this study; however, patients in this study were excluded if they had a body weight of <30 kg. Because this was the first study to assess the dexlansoprazole MR formulation in adolescents, this exclusion criterion was put into place as an added measure of safety to ensure that adolescents enrolled in this study received a dose of dexlansoprazole MR, on a milligrams-per-kilogram basis, that was less than the highest dose administered to adults in the long-term phase 3 studies. Patients who took prescription or nonprescription PPIs, H2RAs, sucralfate, or antacids on a regular or on an as-required basis were to discontinue usage on day −1 and agree to discontinue use throughout the study. Because of the short half-lives of these medications, discontinuation of the medications on day −1 allowed for an appropriate washout period before dexlansoprazole PK assessments on day 7 while minimizing the amount of time the patients would be without therapy.
Exclusion criteria for the study included evidence of present cardiovascular, central nervous system, hepatic, hematopoietic, renal, or metabolic dysfunction; serious allergy, asthma, or allergic rash; a known hypersensitivity to any PPI or any component of the formulation of dexlansoprazole MR capsules; other prescription or nonprescription medication, vitamins, or dietary supplements within 14 days before day 1 (except those which, per protocol, could be continued until day −1); and use of herbal over-the-counter (OTC) medications within 28 days before day 1. Additionally, grapefruit and grapefruit products (including juice) were prohibited during the study. A history of malignant disease, a positive test result for hepatitis B surface antigen or hepatitis C virus antibody, a known history of HIV infection, a history of alcohol abuse or illegal drug use or drug abuse, and use of a product containing nicotine (eg, cigarettes, nicotine patch, chewing tobacco, cigars, nicotine gum, pipe smoking) within 90 days before the first dose of study drug were also grounds for exclusion.
The CYP2C19 isozyme is a polymorphic enzyme that is involved in the metabolism of dexlansoprazole (13). Approximately 6% of the white and African American populations and 13% to 23% of the Asian American population are classified as CYP2C19 poor metabolizers (PMs) (15). Because administration of a PPI with CYP2C19-dependent metabolism may result in higher plasma levels in patients who are PMs (13), patients were screened for CYP2C19 metabolizer status, and identified PMs were excluded from the study.
This investigation was a phase 1, open-label, multicenter, parallel-design study of 2 dexlansoprazole MR capsule doses (30 and 60 mg) for 7 days. Patients were randomized to receive either 30- or 60-mg doses. The study was conducted at 3 sites in the United States and consisted of a screening period up to 28 days before dosing on day 1. It also included a baseline evaluation on day −1, outpatient treatment period (30- or 60-mg dexlansoprazole MR once daily [QD] on days 1–6), and confinement period (days 6–8).
The study was conducted in accordance with the World Medical Association Declaration of Helsinki, the ICH Harmonised Tripartite Guideline for GCP, and all applicable local regulations. Approval for the study was obtained from the institutional review board at each participating investigative site. Written informed consent was obtained from the legally authorized representative (parent/legal guardian) for all of the participants and each participant signed the assent before the performance of any study-related procedure.
During the screening period patients underwent procedures to determine study eligibility, including complete medical and social history, complete physical examination, vital signs, electrocardiography, clinical laboratory tests (hematology, urinalysis, serum chemistry), concomitant medication and adverse event (AE) assessment, fasting serum gastrin and creatinine clearance estimates, serum pregnancy testing for female patients, hepatitis B and C screening, as well as drug, alcohol, and cotinine screening and CYP2C19 genotype testing.
Following the screening visit, and immediately before randomization and entry into the treatment period, patients who satisfied all of the inclusion criteria and none of the exclusion criteria returned to the clinic on Day −1 for baseline evaluation. This included a complete physical examination of vital signs, electrocardiography, and clinical laboratory tests, concomitant medication and AE assessment, fasting serum gastrin and creatinine clearance estimates, serum pregnancy testing for female patients, as well as drug, alcohol, and cotinine screening. At least 16 patients per each age group (12–14 years or 15–17 years old, inclusive) were planned for this study. On day −1, within each age group, patients were randomized in a 1:1 ratio to receive a 7-day supply of dexlansoprazole MR (either 30 or 60 mg). The randomization schedule was generated by Takeda Global Research and Development's (TGRD) Analytical Sciences Department before the start of the trial and provided to the TGRD trial manager and the respective study sites; patients were then assigned to a regimen as the site enrolled patients.
Patients also received daily treatment diaries to record the time, mode of study drug administration (if the subject was unable to swallow the study drug capsule, the study drug was to be administered by sprinkling the capsule granules on 1 tablespoon of applesauce), and the time of the first meal of the day in the daily treatment diary. Patients also recorded in the daily treatment diary any concomitant medications used and any AEs experienced.
Use of concomitant medications was not allowed during the study unless deemed necessary in cases of medical emergency or approved on a case-by-case basis. Occasional use of acetaminophen (paracetamol, up to 2 g/day) for no longer than 2 consecutive days was allowed during the study, except on days 7 and 8. Hormonal contraception and hormone replacement therapy were allowed, as long as the subject had been receiving a stable dose for a minimum of 90 days before day 1. Any use of rescue medication for symptoms of GERD required approval by the investigator.
On days 1 through 6, following an overnight fast, each patient self-administered 1 dexlansoprazole MR capsule (30 or 60 mg) before the morning meal. On day 6, after taking the morning dose of study medication at home, patients returned to the clinic and returned the daily treatment diary and unused study medication.
Patients were confined to the site from day 6 until all of the scheduled procedures were completed on day 8. Within each site during confinement, all of the patients were limited to standardized meals and calories to minimize and reduce intersubject variability. Strenuous activity was not permitted during confinement. Site personnel administered study drug commencing at approximately 0800 hours on day 7, with 240 mL of water and following a minimum 8-hour fast and the recording of predose vital signs.
Blood samples for the assessment of dexlansoprazole plasma pharmacokinetics were collected for 24 hours following dexlansoprazole MR administration on study day 7, at 0 hours (predose), and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, and 24 hours postdose. Blood samples were collected into chilled evacuated tubes containing dipotassium ethylenediamine tetraacetic acid and were centrifuged at 4°C to separate the plasma from the cells. The plasma samples were stored at −20°C until analysis. Concentrations of dexlansoprazole in human plasma were measured using a proprietary, validated liquid chromatography-tandem mass spectrometry assay at Pharmaceutical Product Development Inc (Middleton, WI). The assay had a validated concentration range of 2 to 2000 ng/mL. The stability of dexlansoprazole during the processing and storage of the samples was established during the validation of the assay at PPD. Dexlansoprazole plasma concentrations were tabulated, and concentrations below the lower limit of quantitation were set to zero for PK analysis and summary statistics. PK parameters (Table 1) were estimated for each individual patient to address the primary objective of the study.
Safety variables included AEs, clinical laboratory tests (hematology, serum chemistry, and urinalysis), fasting gastrin concentration, vital signs, physical examination, and electrocardiogram (ECG) results. A treatment-emergent adverse event (TEAE) was defined as an AE that started or worsened after receiving the first dose of study drug and within 30 days after the last dose of study drug. An AE was defined as a treatment-related AE if the investigator considered it a reasonable possibility that an event was the result of a study procedure. At each study visit, the investigator assessed whether any AEs had occurred. Patients could report events occurring at any other time. All of the events, whether reported by the patient or observed by the investigator, were documented and characterized as mild (transient and easily tolerated), moderate (caused discomfort and interrupted usual activities), or severe (caused considerable interference with usual activities).
A sample size of 36, with 18 patients per dose group and at least 16 patients per age group (12–14 years old and 15–17 years old), was planned for this study. The number of patients, along with the intense PK sampling in each subject, was expected to be sufficient for the characterization of the PK profile of dexlansoprazole. Summary statistics were performed using SAS version 9.1.3 (SAS Institute, Cary, NC). Continuous data were summarized using number of patients (N), mean, standard deviation (SD), median, minimum, and maximum. Where appropriate, percent coefficient of variation (% CV) and harmonic mean values were also included in the summary of certain PK parameters. Categorical data were summarized using the number and percentage of patients for each category wherever appropriate. All of the computations were performed before rounding. Unless specified, baseline was defined as the pretreatment assessment immediately before the start of the study drug. No statistical comparison was performed for the PK parameters between dose groups.
Linear and semilogarithmic plots of the mean plasma dexlansoprazole concentrations were generated for each regimen. PK parameters were derived using noncompartmental methods with WinNonlin Professional Version 5.2 (Pharsight Corp, Mountain View, CA). PK parameters (Table 1) of dexlansoprazole were determined for both doses on day 7 from the concentration time profiles for all evaluable patients. Actual sampling times, rather than scheduled sampling times, were used in the computation of PK parameters. Plasma PK parameters of dexlansoprazole were summarized by dose. In addition, the harmonic means were computed for half-life (T1/2). Dose-normalized Cmax and AUCs were also summarized by dose. Patients with at least 1 estimable PK parameter for dexlansoprazole on day 7 were included in the summary.
All of the safety assessments, including AEs, clinical laboratory evaluations, vital signs, 12-lead ECG results, and physical examination, were summarized with descriptive statistics by regimen as appropriate. All of the patients who received at least 1 dose of study drug were included in the safety evaluation.
This study was conducted from May 31, 2009 to September 10, 2009, at 3 investigative units that conduct a variety of phase 1 studies. Of the 76 adolescents screened, a total of 14 male and 22 female adolescents with a mean age of 14.6 years were randomly assigned to either 30- or 60-mg dexlansoprazole MR (QD) for 7 days. All of the 36 patients (18 patients per dose group) completed the study and were included in the safety analysis. One patient in the dexlansoprazole MR 30-mg (QD) group was excluded from the PK analysis set because most of the PK samples were not collected on day 7.
Demographic and baseline characteristics were comparable between the 2 treatment groups (Table 2). The median age was 14.5 years (range 12–17), and the median body mass index was 22.5 kg/m2 (range 17–33). Pretreatment CYP2C19 genotype testing indicated that all 36 patients were extensive metabolizers. Fourteen of the 36 patients reported medication use within 38 days before the screening period; the most common medication usage reported included ibuprofen and calcium carbonate. Four of the 36 patients took concomitant medication during the study. The most common medication usage during the study was acetaminophen, taken by 2 patients to treat AEs of headache.
Seventeen of the 18 patients who completed the 30-mg treatment and all 18 patients who completed the 60-mg treatment and who had complete PK profiles were included in the PK and statistical analyses. Study day 7 plasma dexlansoprazole concentrations versus time plots following administration of dexlansoprazole MR 30 and 60 mg in adolescent patients are presented in Figure 1. The time course of dexlansoprazole plasma concentrations displayed 2 distinct peaks, demonstrating the release characteristics of the DDR capsule formulation. Corresponding PK parameter estimates for dexlansoprazole are presented in Table 3. In patients 12 to 17 years old, the mean time to Cmax (Tmax) values were 4.65 and 3.31 hours following administration of dexlansoprazole MR 30 and 60 mg, respectively. The overall exposure of dexlansoprazole after administration of dexlansoprazole MR 60 mg, as measured by mean Cmax and AUC values, was slightly less than double the exposure from the 30-mg dose (Table 3). For the 30- and 60-mg doses, dexlansoprazole harmonic mean T1/2 values were 1.32 and 2.04 hours, respectively, and mean oral clearance (CL/F) was 12.8 and 15.3 L/hour, respectively.
A total of 36 patients were randomized and received all 7 doses of study medication (30- or 60-mg dexlansoprazole MR). No patients discontinued treatment during the study and there were no deaths or other nonfatal AEs. The number of patients who experienced at least 1 AE is summarized in Table 4. The most common TEAEs were abdominal pain, vomiting, headache, dizziness, and presyncope (vasovagal reaction). All of the AEs during the study were considered to be of mild severity. The incidence of AEs considered related to treatment was 22% and 11% in the dexlansoprazole MR 30- and 60-mg groups, respectively. AEs considered related to treatment were abdominal pain (22% in the 30-mg group but not observed in the 60-mg group), vomiting (not observed in the 30-mg group and 2 patients (11%) in the 60-mg group), and headache (not observed in the 30-mg group and 6% in the 60-mg group). Both patients who reported vomiting did so on day 1; therefore, the report of vomiting would not have any effect on the PK because vomiting did not occur on the day the PK was assessed (day 7).
There were no clinically significant changes from baseline in any laboratory parameter or abnormal laboratory test result. After 7 days of treatment, the mean changes from baseline in fasting serum gastrin were increases of 57.3 pg/mL in the 30-mg group and 41.4 pg/mL in the 60-mg group. None of the 36 patients had abnormal clinically significant vital sign measurements, ECG results, or drug-related physical examination changes during the study.
The PK, pharmacodynamic, and safety profiles of dexlansoprazole following administration of dexlansoprazole MR in adults have been studied extensively (12,14,16–18); however, before this study, dexlansoprazole MR had not been studied in patients younger than 18 years. The course of GERD and the effects of the PPI class of drugs have been shown to be similar in adults and pediatric patients 12 to 17 years of age (3), and PPIs have been shown to be an effective treatment for GERD in both children older than 1 year and adults (5,13,19,20). Therefore, it is expected that dexlansoprazole MR will be an effective treatment for GERD in the pediatric population. This expectation is further supported by the well-established safety and efficacy profile of lansoprazole, and the fact that dexlansoprazole constitutes >80% of circulating drug after oral administration of lansoprazole (21). The present study provides the basis for dosing recommendations in the phase 2 clinical studies that will evaluate safety and effectiveness of dexlansoprazole in the pediatric population.
The time course of dexlansoprazole plasma concentrations in the 12- to 17-year-old adolescent patients displayed 2 distinct peaks, reflective of the release characteristics of the DDR capsule formulation, and were comparable to those observed in previous studies of healthy adult subjects (12,13,18) (Fig. 2). Mean PK parameters from the present study and pooled PK data from dexlansoprazole MR administered to healthy adults are presented in Table 3(12,18). Although minor differences between the mean dexlansoprazole PK values for the 30 mg dose in 12- to 17-year-old patients and the pooled adult data are apparent, overall the pharmacokinetics of dexlansoprazole 30-mg MR dose are generally similar between adolescent patients weighing >30 kg with symptomatic GERD and healthy adults. Mean dexlansoprazole Cmax and AUC values in adolescents were approximately 88% to 105% of the respective mean values observed in healthy adults. The dexlansoprazole Tmax was slightly greater, half-life was slightly shorter, and CL/F was slightly faster in the adolescent patients, compared with pooled adult PK data in healthy volunteers. Differences in the pharmacokinetics of dexlansoprazole MR 60-mg dose between adolescents and the pooled adult data were moderately greater than those observed for the 30-mg dose (Table 3). Considering the small number of adolescent patients for whom data were available (17 in the 30-mg dose group, and 18 in the 60-mg dose group), however, the variability of the dexlansoprazole PK parameter estimates (percent coefficient of variation of 46% to 63% in adolescents and 37% to 60% in healthy adults), and the overall similarity of the pharmacokinetics observed for the 30-mg dose, the magnitude of the PK differences between adolescents and adults observed for the 60-mg dose are unlikely to be clinically relevant.
In adults, PPIs are potent inhibitors of gastric acid secretion because they irreversibly block the final common path of acid production, the activated proton pumps; the estimated half-life of the proton pump is 50 hours (22). PPIs inhibit the secretion of H+ ions in the stomach by inhibiting the (H+, K+)-ATPase enzyme (proton pump) on the secretory surface of the gastric parietal cell, thereby inactivating the proton pump for its remaining half-life. To be most effective, PPIs must be present in high concentrations when the pumps are activated, although not all proton pumps are stimulated at the same time. Furthermore, exposure of the active proton pumps to drug is limited because PPIs have a relatively short half-life (1–2 hours).
The pharmacodynamics of dexlansoprazole was not assessed in this study. However, the PK and pharmacodynamic profiles of lansoprazole in adolescent patients with GERD have been shown to be similar to those observed in healthy adults (10,11). In adults, the dexlansoprazole MR formulation produces a dual-peaked PK profile that provides an extended duration of pharmacologically active dexlansoprazole concentration in plasma, and statistically significantly higher mean 24-hour pH as compared with lansoprazole (12). The present study demonstrated the similarity of the PK profiles of dexlansoprazole MR in adolescent patients with GERD and healthy adult subjects. This suggests that the pharmacodynamic response in such adolescent patients following administration of dexlansoprazole MR 30 and 60 mg would be similar to the pharmacodynamic response seen in healthy adults at the same doses.
Dexlansoprazole MR 30- and 60-mg doses were well tolerated in patients 12 to 17 years of age. All of the 36 patients completed the study; 21 total AEs were reported during the 7-day treatment period by 12 of the 36 patients. All of the AEs during the study were considered to be of mild severity. The most common TEAEs were abdominal pain, vomiting, headache, dizziness, and presyncope. AEs considered related to treatment were abdominal pain, vomiting, and headache, consistent with the AE profile observed in adults and commonly observed with PPIs.
There were no clinically significant changes from baseline in any laboratory parameter. Similarly, none of the 36 patients had abnormal clinically significant vital sign measurements, ECG results, or drug-related physical examination changes during the study.
In summary, the overall exposure to dexlansoprazole following administration of dexlansoprazole MR 60 mg, as measured by mean Cmax and AUC values, was slightly less than double the exposure from dexlansoprazole MR 30 mg in adolescent patients 12 to 17 years of age with symptomatic GERD. The PK profiles of dexlansoprazole following administration of dexlansoprazole MR 30 and 60 mg in adolescent patients were not appreciably different from the pooled PK parameters summarized from the healthy adults in phase 1 studies. Both 30- and 60-mg doses of dexlansoprazole MR were well tolerated in adolescent patients.
The authors acknowledge and thank the participating principal investigators at the 3 phase 1 sites who oversaw procedures and cared for the patients in this study: Apinya Bee Vutikullird, DO, West Coast Clinical Trials, LLC, Cypress, CA (specialty: osteopathic medicine, resident chief of gynecology for family medicine); Dennis S. Riff, MD, FACG, Advanced Clinical Research Institute, Anaheim, CA (specialty: gastroenterologist); and Bradley D. Vince, DO, Vince and Associates Clinical Research Overland Park, KS (specialty: osteopathic medicine, residency in psychiatry).
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