Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

BACKGROUND: Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. CLINICAL TRIALS: The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. THERAPEUTIC ADVANCE: Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

Review of lisdexamfetamine dimesylate in children and adolescents with attention deficit/hyperactivity disorder.

OBJECTIVE: Lisdexamfetamine dimesylate is a stimulant prodrug with low abuse and diversion potential that is used in treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults. This current literature review article aims to examine safety and efficacy of LDX in children and adolescents for the treatment of ADHD based on currently available data. METHODS: Relevant English language articles were identified through computerized searches of the MEDLINE database (PubMed and EMBASE) and clinical trials registry up to January 2020 using the following search terms: lisdexamfetamine dimesylate, pro-drug stimulant, attention-deficit and hyperactivity disorders, ADHD, safety, efficacy, children, adolescents, Vyvanse. Forty-two articles were reviewed, 34 of which were included into this review, selected by the limit "clinical trials". This article represents the pharmacological profile, efficacy and safety data of LDX for the treatment of ADHD in children and adolescents. RESULTS: The collection of studies reviewed identified that LDX was both safe and efficacious in the treatment of ADHD. The most commonly exhibited side effects were appetite suppression, weight loss, headache and insomnia. In comparison to placebo, LDX significantly improved ADHD symptoms and overall quality of life in children and adolescents. In comparison to atomoxetine, LDX showed statistically significant improvements in inattention, impulsivity, and activities of daily living. In comparison to OROS-MPH and placebo, LDX and OROS-MPH showed improvements with the CGI-I score, and ADHD-RS-IV, however, LDX was superior. CONCLUSION: Patients have seen statistically significant improvements in their ADHD symptomatology in the classroom environment, health related quality of life, and their overall behavior in comparison to placebo, atomoxetine, and OROS-MPH. However, clinical judgment should be utilized when prescribing LDX due to patient specific needs and the side effect profile.

Review of Lisdexamfetamine Dimesylate in Adults With Attention-Deficit/Hyperactivity Disorder.

Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant used for the treatment of attention-deficit/hyperactivity disorder (ADHD) dosed once daily. Due to its long-acting properties, LDX remains pharmacologically inactive until an enzymatic process predominantly associated with red blood cells converts it to the active ingredient, d-amphetamine and the amino acid lysine. The efficacy of LDX over placebo has been demonstrated in several studies in adults with moderate to severe ADHD with significant improvements noted in ADHD rating scales, Clinical Global Improvement scores, and assessments of executive function, for all doses of LDX (30-70 mg daily). Lisdexamfetamine dimesylate has demonstrated efficacy at 14 hours post dose in adults and may be used as a long-acting stimulant for managing ADHD symptoms, which may extend late into the day. Lisdexamfetamine dimesylate has demonstrated a safety profile consistent with long-acting stimulants use. Relevant English language articles were identified through computerized searches of MEDLINE (PubMed and EMBASE) from 1995 to 2016 using the following search terms: lisdexamfetamine dimesylate, attention-deficit hyperactivity disorder, NRP104, and Vyvanse.

Lisdexamfetamine in the treatment of adolescents and children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder is one of the most common neurobehavioral disorders defined by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity. Symptoms begin in childhood and may persist into adolescence and adulthood. Currently available pharmacological treatment options for attention-deficit/hyperactivity disorder in children and adolescents include stimulants that are efficacious and well tolerated; however, many of these preparations require multiple daily dosing and have the potential for abuse. Lisdexamfetamine dimesylate, the first prodrug stimulant, was developed to provide a longer duration of effect. It demonstrates a predictable delivery of the active drug, d-amphetamine, with low interpatient variability, and has a reduced potential for abuse. A literature search of the MEDLINE database and clinical trials register from 1995-2011, as well as relevant abstracts presented at annual professional meetings, on lisdexamfetamine dimesylate in children and adolescents were included for review. This article presents the pharmacokinetic profile, efficacy, and safety of lisdexamfetamine dimesylate for the treatment of attention-deficit/hyperactivity disorder in children and, more recently, in adolescents.

The efficacy and safety profile of lisdexamfetamine dimesylate, a prodrug of d-amphetamine, for the treatment of attention-deficit/hyperactivity disorder in children and adults.

BACKGROUND: Lisdexamfetamine dimesylate (LDX) is a once-daily medication approved by the US Food and Drug Administration for the management of attention-deficit/hyperactivity disorder (ADHD) in children (aged 6-12 years) and adults. OBJECTIVE: This article reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of LDX. METHODS: Studies, abstracts, reviews, and consensus statements published in English were identified through computerized searches of MEDLINE (1966-August 2008) and International Pharmaceutical Abstracts (1977-August 2008) using search headings lisdexamfetamine dimesylate, attention-deficit/hyperactivity disorder, NRP 104, NRP104-201, NRP104-301, NRP104-302, NRP104-303, and stimulant. Selected information provided by the manufacturer of LDX was included, as were all pertinent clinical trials. The reference lists of identified articles were also searched for pertinent information. Relevant abstracts presented at annual professional meetings were included as well. RESULTS: Several studies have evaluated the pharmacokinetics of LDX in pediatric patients (6-12 years of age) and healthy adults with ADHD. LDX, a prodrug that is therapeutically inactive until metabolized in the body to dextroamphetamine (d-amphetamine), follows linear pharmacokinetics at therapeutic doses (30-70 mg). The efficacy of LDX in the treatment of ADHD was established on the basis of 1 long-term and 2 short-term controlled clinical trials in children who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for ADHD (either the combined or the hyperactive-impulsive subtype) and in 1 clinical trial with adults with ADHD. The efficacy trials in children found significant improvements in scores on the Swanson, Kotkin, Agler, M-Flynn, and Pelham deportment sub-scales, the Permanent Product Measure of Performance (Attempted and Correct), and the ADHD Rating Scale Version IV (ADHD-RS-IV) compared with placebo (all, P < 0.001). In the clinical studies designed to measure duration of effect, LDX, compared with placebo, provided efficacy for a full treatment day, up through and including 6 PM, based on parent ratings (Conners' Parent Rating Scale-Revised Short Form) in the morning, afternoon, and early evening (all, P < 0.001). Data from a long-term, open-label extension study that assessed the safety, tolerability, and efficacy of LDX for up to 12 months found LDX treatment resulted in significant improvement (>60%) from baseline in the ADHD-RS-IV at end point (P < 0.001), with good tolerability. The trial in adults found significant improvements in ADHD-RS scores at end point in patients receiving LDX (30,50, and 70 mg) (P < 0.001 for all active doses); significant improvements in ADHD-RS (using adult prompts) scores were observed at each postbaseline weekly assessment, with improvements noted within the first week in all active treatment arms. Results from human abuse liability studies noted that LDX had lower abuse-related drug-liking scores compared with immediate-release d-amphetamine at equivalent doses. The most common adverse events reported with LDX were typical of amphetamine products and included decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight loss, and nausea. CONCLUSIONS: Current evidence supports the efficacy and tolerability of LDX as a treatment option for the management of children (aged 6-12 years) and adults with ADHD. As such, LDX may be an integral part of a total treatment program for ADHD that can include other measures such as psychological, educational, and social interventions.

Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia.

OBJECTIVE: This paper reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of the nonbenzodiazepine cyclopyrrolone agent eszopiclone in the management of adult patients with insomnia. METHODS: Recent studies, abstracts, reviews, and consensus statements published in English were identified through searches of MEDLINE (1966-December 2005), International Pharmaceutical Abstracts (1970 December 2005), and PharmaProjects (1990-December 2005) using the search terms eszopiclone, cyclopyrrolone, insomnia, nonbenzodiazepine, and zopiclone enantiomer. Selected information provided by the manufacturer of eszopiclone was included, as were all pertinent clinical trials. RESULTS: Eszopiclone is rapidly absorbed after oral administration, with Tmax achieved within approximately 1 hour and a terminal-phase elimination half-life of approximately 6 hours. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Eszopiclone is extensively metabolized by oxidation and demethylation. In vitro studies have indicated that the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; therefore, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Eszopiclone is excreted in the urine as racemic zopiclone at <10% of the orally administered dose. Six Phase III clinical trials were identified that evaluated the safety profile and efficacy of eszopiclone, 1 in healthy subjects with transient insomnia and 5 in patients with primary chronic insomnia (3 in younger adults and 2 in the elderly). In the trials in younger adults, eszopiclone significantly improved sleep efficiency, sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened weekly, total sleep time, and quality and depth of sleep compared with placebo (P<0.05). In the trials in elderly patients, who received eszopiclone 2 mg or placebo for 2 weeks, eszopiclone was associated with significantly shorter sleep latency compared with placebo (P<0.004), as well as a significant decrease in the cumulative number of naps (P<0.05). The most commonly reported drug-related, dose-responsive adverse event in clinical trials of eszopiclone 2 and 3 mg was bitter taste (17% and 34%, respectively), followed by dizziness (5% and 7%) and dry mouth (5% and 7%). Somnolence occurred at an incidence of 4% to 9% with both doses. Tolerance or rebound insomnia was not reported. CONCLUSIONS: Eszopiclone represents an effective and well-tolerated option for the treatment of insomnia. In the absence of published studies comparing eszopiclone with similar hypnotic agents (eg, zolpidem, zaleplon, zopiclone), it is not yet possible to evaluate its efficacy relative to other agents used for insomnia.

Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation.

BACKGROUND: The fibric acid derivative fenofibrate is indicated as an adjunct to dietary modification in adults with primary hypercholesterolemia or mixed dyslipidemia (types IIa and IIb hyperlipidemia, Fredrickson classification) to reduce levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and apolipoprotein (apo) B, and to increase levels of high-density lipoprotein cholesterol (HDL-C) and apo A. It is also indicated as adjunctive therapy to diet for the treatment of hypertriglyceridemia (types IV and V hyperlipidemia). Initially approved in the United States in a micronized capsule formulation, fenofibrate is now available in a new "suprabioavailable" tablet formulation that has increased bioavailability, achieving equivalent plasma concentrations at lower doses. The 67- and 200-mg micronized capsules can be considered equivalent to the 54- and 160-mg suprabioavailable tablets, respectively. OBJECTIVE: This paper reviews the pharmacologic properties, clinical usefulness, and safety profile of fenofibrate in the management of dyslipidemias. METHODS: Recent studies, abstracts, reviews, and consensus statements published in the English-language literature were identified through searches of MEDLINE (1966-January 2002), International Pharmaceutical Abstracts (1970-January 2002), and PharmaProjects (1990-January 2002) using the search terms fenofibrate, fibrates, hyperlipidemia, hypertriglyceridemia, and dyslipidemia. RESULTS: Fenofibrate is well absorbed after oral administration, with peak plasma levels attained in 6 to 8 hours. The absolute bioavailability of fenofibrate cannot be determined due to its being virtually insoluble in aqueous media suitable for injection; however, after oral administration of a single dose of radiolabeled fenofibrate, approximately 60% of the dose appeared in urine, primarily as fenofibric acid and its glucuronated conjugate, and approximately 25% was excreted in the feces. The apparent volume of distribution is 0.89 L/kg in healthy volunteers, and protein binding is approximately 99% in healthy and hyperlipidemic patients. Neither fenofibrate nor fenofibric acid appears to undergo significant oxidative metabolism in vivo. Fenofibric acid has a half-life of 20 hours. Fenofibrate is effective in lowering TG levels and increasing HDL-C levels. Its LDL-C-lowering effect is greater than that of gemfibrozil. Adverse effects of fenofibrate appear to be similar to those of other fibrates, including gastrointestinal symptoms, cholelithiasis, hepatitis, myositis, and rash. Fenofibrate therapy has been associated with increases in serum aminotransferase levels, and clinical monitoring of these markers of liver function should be performed regularly. CONCLUSIONS: Fenofibrate is effective in reducing levels of TG, TC, and LDL-C, and increasing levels of HDL-C in patients with dyslipidemias. Its efficacy and tolerability in the treatment of hypertriglyceridemia and combined hyperlipidemia have been demonstrated in numerous clinical trials. Its use is accompanied by a low incidence of adverse effects and laboratory abnormalities. Fenofibrate protects against coronary heart disease not only through its effects on lipid parameters but also by producing alterations in LDL structure and, possibly, alterations in the various hemostatic parameters. Its uricosuric property may prove to be a useful adjunctive attribute.