Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.

Lemborexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia and is under investigation for treating other sleep disorders. Here we summarize pharmacokinetic, pharmacodynamic, and safety data from 3 randomized, double-blind, placebo-controlled phase 1 studies: single ascending doses in healthy adults (Study 001; 1-200 mg; N = 64), multiple ascending doses in healthy and elderly adults (Study 002; 2.5-75 mg; N = 55), and multiple doses in healthy white and Japanese adults (Study 003; 2.5-25 mg; N = 32). Lemborexant exposure increased with increasing dose. The time to maximum concentration ranged from approximately 1 to 3 hours for the 5- and 10-mg doses. The mean effective half-life was 17 hours for lemborexant 5 mg and 19 hours for lemborexant 10 mg. The plasma concentration at 9 hours postdose was 27% of the maximum concentration following multiple dosing with lemborexant 10 mg. There were no clinically relevant effects on next-morning residual sleepiness (Karolinska Sleepiness Scale, Digital Symbol Substitution Test, Psychomotor Vigilance Test) for doses through 10 mg/day, indicating no effect of residual plasma concentrations on next-day residual effects. Lemborexant was well tolerated across the doses tested. There were no clinically relevant effects of age, sex, or race on lemborexant pharmacokinetics, pharmacodynamics, or safety. These results suggest that lemborexant at doses through 25 mg provides an overall pharmacokinetic, pharmacodynamic, and safety profile suitable for obtaining the target pharmacologic effect supporting treatment of insomnia while minimizing residual effects during wake time.

Middle-of-the-night administration of sleep medication: a critical review of the effects on next morning driving ability.

STUDY OBJECTIVES: Sleep maintenance problems are common, hence treatments enabling patients to fall asleep more rapidly after middle-of-the-night (MOTN) awakenings, without impairing next morning alertness, are needed. This literature review compares the effects of MOTN administration of various hypnotics on morning driving ability, a potentially dangerous daily activity under conditions of impairment. METHODS: A literature search was conducted identifying on-the-road driving studies examining the effects of MOTN administration of hypnotics on morning driving performance. In a standardized 100-km highway driving test in normal traffic, subjects were instructed to drive with a steady lateral position and constant speed of 95 km/h. The primary outcome measure of the driving test is the Standard Deviation of Lateral Position (SDLP, cm), i.e. weaving of the car. RESULTS: Four driving studies were identified. Driving performance after MOTN administration of traditional benzodiazepine hypnotics was not examined. Zolpidem (10 mg and 20 mg, oral immediate release tablets) significantly impaired driving in a dose-dependent manner, when tested 4 hours after MOTN administration. Also, gaboxadol (15 mg) and zopiclone (7.5 mg) significantly impaired next-morning driving after MOTN administration. In contrast, sublingual zolpidem (3.5 mg) and zaleplon (10 mg and 20 mg) did not significantly affect driving 4 hours after MOTN administration. CONCLUSION: Driving was not affected 4 hours after MOTN administration of sublingual zolpidem (3.5 mg) or zaleplon (10 mg and 20 mg). Significant driving impairment was found after MOTN administration of zolpidem (10 and 20 mg), gaboxadol (15 mg), and zopiclone (7.5 mg).

Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration.

The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of zolpidem after administration of a buffered zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that zolpidem clearance is lower in females than in males. PD effects of zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.

Comparison of pharmacokinetic profiles of zolpidem buffered sublingual tablet and zolpidem oral immediate-release tablet: results from a single-center, single-dose, randomized, open-label crossover study in healthy adults.

BACKGROUND: A zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. OBJECTIVE: The aim of this study was to compare the zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral zolpidem in healthy female and male adults. METHODS: This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral zolpidem in healthy adults. RESULTS: The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both zolpidem formulations were generally well tolerated by both genders. CONCLUSIONS: Systemic exposure of zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.

Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study.

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society.

The ADAS-cog in Alzheimer's disease clinical trials: psychometric evaluation of the sum and its parts.

BACKGROUND: The Alzheimer's Disease Assessment Scale Cognitive Behavior Section (ADAS-cog), a measure of cognitive performance, has been used widely in Alzheimer's disease trials. Its key role in clinical trials should be supported by evidence that it is both clinically meaningful and scientifically sound. Its conceptual and neuropsychological underpinnings are well-considered, but its performance as an instrument of measurement has received less attention. Objective To examine the traditional psychometric properties of the ADAS-cog in a large sample of people with Alzheimer's disease. METHODS: Data from three clinical trials of donepezil (Aricept) in mild-to-moderate Alzheimer's disease (n=1421; MMSE 10-26) were analysed at both the scale and component level. Five psychometric properties were examined using traditional psychometric methods. These methods of examination underpin upcoming Food and Drug Administration recommendations for patient rating scale evaluation. RESULTS: At the scale-level, criteria tested for data completeness, scaling assumptions (eg, component total correlations: 0.39-0.67), targeting (no floor or ceiling effects), reliability (eg, Cronbach's α: = 0.84; test-retest intraclass correlations: 0.93) and validity (correlation with MMSE: -0.63) were satisfied. At the component level, 7 of 11 ADAS-cog components had substantial ceiling effects (range 40-64%). CONCLUSIONS: Performance was satisfactory at the scale level, but most ADAS-cog components were too easy for many patients in this sample and did not reflect the expected depth and range of cognitive performance. The clinical implication of this finding is that the ADAS-cog's estimate of cognitive ability, and its potential ability to detect differences in cognitive performance under treatment, could be improved. However, because of the limitations of traditional psychometric methods, further evaluations would be desirable using additional rating scale analysis techniques to pinpoint specific improvements.

Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study.

BACKGROUND: Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. OBJECTIVE: The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. METHODS: This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for > or =12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. RESULTS: The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0-138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Delta in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Delta in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs -1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. CONCLUSIONS: In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.

Sleep in women across the life cycle from adulthood through menopause.

Studies of sleep across the life cycle in women have utilized both survey and polysomnographic techniques, but have tended to be of small sample size with diverse methodology. As a result, definitive conclusions about the impact of the menstrual cycle and use of oral contraceptives on sleep parameters cannot yet be made. Sleep disruption during pregnancy and postpartum is nearly universal, but effective and practical countermeasures are still needed. Longitudinal studies of sleep in the postpartum period are also lacking. Menopause is associated with insomnia due to several factors including hot flashes, mood disorders and increased sleep-disordered breathing. The use of hormone replacement therapy to treat sleep and other variables is an active area of investigation. In summary, much research is required to fully elucidate the impact of the life cycle on sleep parameters in women.