The purpose of this study is to determine the pharmacokinetic profile, safety, and tolerability of ramelteon in adolescents with insomnia, children with Attention Deficit Hyperactivity Disorder (ADHD) associated with insomnia and gender- and race-matched healthy adults.
Ramelteon is a treatment for insomnia approved for use in the United States (US) in July 2005 and in the Philippines and Indonesia in 2008. It is currently under development in the European Union (EU) and Japan. Ramelteon is marketed in the US as ROZEREM® for the treatment of insomnia characterized by difficulty with sleep onset in patients over 18 years of age. In adolescents, the form of sleep onset and/or sleep maintenance insomnia, defined as psychophysiologic insomnia, is similar to adults, and more appropriate for treatment with pharmacological intervention when compared to insomnia in children younger than 12 years of age. In psychophysiologic insomnia, the individual develops conditioned anxiety around difficulty falling or staying asleep, which leads to heightened physiologic and emotional arousal and further compromises the ability to sleep. In children over the age of 12, insomnia is more likely to be persistent and have identifiable consequences. In addition, there is less variability in normative sleep data for this age group than in younger children. Sleep disturbances are also common in children. Specifically, insomnia associated with ADHD in children is very common with a reported prevalence of 28% in medication-free children with ADHD. This study is to characterize the pharmacokinetics (PK) and safety profile of a 4 or 8 mg dose of ramelteon in adolescents who are between 12 to 17 years of age (prior to the 18th birthday) with insomnia characterized by difficulty with sleep initiation, and in pediatrics who are between 6 to 11 years of age who have insomnia associated with ADHD. These profiles will be compared with those of healthy adults aged 18 to 50 years who are matched by race and gender receiving an 8 mg dose of ramelteon. This open-label study is designed in accordance with the recommendations of the FDA and ICH guidances for pediatric PK studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Masking
NONE
Enrollment
56
Ramelteon tablets, orally for one day only.
Unnamed facility
Overland Park, Kansas, United States
Unnamed facility
Kalamazoo, Michigan, United States
Maximum Observed Serum Concentration (Cmax)
Maximum observed serum concentration (Cmax) is the peak serum concentration of ramelteon and its metabolite (M-II) after administration, obtained directly from the serum concentration-time curve.
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Time to Reach Maximum Serum Concentration (Tmax)
Tmax: Time to reach the maximum serum concentration (Cmax) of ramelteon and its metabolite M-II, equal to time (hours) to Cmax.
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Area Under the Serum Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc])
Area under the serum concentration-time curve from time 0 to time of last quantifiable concentration (tlqc) of ramelteon and its metabolite M-II, calculated using the linear trapezoidal rule.
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC[0-inf])
Area under the serum concentration-time curve from time zero extrapolated to infinity for ramelteon and its metabolite M-II. The terminal area from the last quantifiable concentration (lqc) to infinity is calculated by approximation: lqc / terminal elimination rate constant (λz).
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Apparent Clearance After Oral Administration (CL/F)
Apparent oral clearance of drug from the serum calculated as: CL/F = Dose / Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC\[0-inf\]).
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
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Terminal Elimination Rate Constant (λz)
The rate at which ramelteon and its metabolite M-II are eliminated from the body, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Terminal Elimination Half-life (T1/2)
Terminal phase elimination half-life (T1/2) for ramelteon and its metabolite M-II is the time required for half of the drug to be eliminated from the serum, calculated as T1/2 = natural logarithm of 2 (ln\[2\]) / Terminal elimination rate constant (λz).
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Apparent Volume of Distribution (Vz/F)
Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as Vz/F = Apparent oral clearance (CL/F) / Terminal elimination rate constant (λz).
Time frame: Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose.
Number of Participants With Adverse Events (AE)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it did not necessarily have to have a causal relationship with this treatment. The different categories of intensity (severity) were characterized as follows: Mild: The event was transient and easily tolerated by the participant. Moderate: The event causes the participant discomfort and interrupted usual activities. Severe: The event causes considerable interference with the participant's usual activities.
Time frame: Day 1 to Day 15
Number of Participants With Clinically Significant Laboratory Findings
Laboratory samples were collected at Screening, Check-in (Day 1), and Day 2 or Early Termination for assessment of hematology, chemistry, and urinalysis.
Time frame: Screening, Day 1, Day 2 and Day 4
Number of Participants With Clinically Significant Vital Signs
Vital signs included oral body temperature, pulse and blood pressure (taken after 5 minutes in the sitting position). Vital signs measurements were determined to be clinically significant according to predefined criteria.
Time frame: Screening, Day 1, Day 2 and Day 4
Number of Participants With Clinically Significant Electrocardiogram Findings
A standard 12-lead electrocardiogram (ECG) was recorded at Screening, Day 2, and at Final Visit (Day 4). The investigator interpreted the ECG using one of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant.
Time frame: Screening, Day 2 and Day 4
Number of Participants With Clinically Significant Physical Examination Results
A complete physical examination was performed for each participant at Screening, Check-in (Day 1), Day 2, and Final Visit (Day 4) or Early Termination. The examination consisted of a review of the following body systems: eyes; ears, nose, and throat; respiratory; gastrointestinal; extremities; musculoskeletal; cardiovascular; nervous; and dermatological.
Time frame: Screening, Day 1, Day 2 and Day 4