Background:
Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan.
Aims:
This study was conducted to ...investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant.
Methods:
This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory.
Results:
Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment–emergent adverse event was somnolence.
Conclusion:
Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant.
Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, ...small‐peptidic structure limits CNS entry, minimizing potential CNS‐mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single‐center, randomized, double‐blind, placebo‐controlled, three‐way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end‐tidal carbon dioxide (ETCO2) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO2) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO2 or reduced SpO2 primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4‐h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO2, SpO2, or respiratory rate. The most commonly reported treatment‐emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.
Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, ...these components are recommended to be administered as a fixed‐dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open‐label, bioequivalence (BE) studies and one drug‐drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two‐way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (Cmax) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of Cmax for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well‐tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co‐administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.
Abuse liability studies usually measure drug liking using 100-mm visual analog scales (VAS), presented as unipolar (liking measured on entire scale) or bipolar (liking and disliking measured with a ...neutral midpoint). These 2 types of VAS were compared using drug liking ratings from a randomized double-blind crossover study of immediate-release and controlled-release oxycodone in 2 cohorts of nondependent recreational opioid users. Cohort 1 (n = 19) received intact oxycodone 40 mg, intact OxyContin
40 and 80 mg, crushed OxyContin
40 mg, and placebo, while cohort 2 (n = 16) received intact oxycodone 20, 40, and 80 mg and placebo. In general, bipolar and unipolar ratings were positively correlated (r = 0.72) for all values (n = 2,477). E
for both scales generally had higher correlation than individual responses for active drug or placebo. The correlation for individual scores after placebo treatment for the 2 scales was poor in both cohorts (r = -0.11, cohort 1 and r = 0.17, cohort 2). Both scales performed similarly within the context of the study, but bipolar scales can also assess disliking, which may be a consideration depending on anticipated drug effects. Appropriate participant training on the use of these scales is also necessary to reduce variability.
To identify key characteristics and habits of recreational opioid users.
The data were compiled from volunteers who participated in clinical studies at a contract research organization in Toronto, ...Ontario, Canada.
Data were collected from 5,018 male and female recreational opioid users via telephone and face-to-face screening interviews. Five recreational opioid users participated in a live interview broadcast on the internet.
Demographic data, recreational drug use history, routes of recreational drug administration, alcohol use, and smoking status. A subset of the demographic information and recreational drug use history was summarized separately using data collected between 2013 and 2016 from 114 recreational opioid users who were not dependent on opioids. Interview excerpts were included from five recreational opioid users who described their real-world experiences with drug abuse, including the impact of abuse-deterrent opioid formulations on their drug abuse behavior.
The preferred route of administration of opioids was oral (52 percent), followed by intranasal (36 percent), intravenous (10 percent), and buccal (chewing on a patch; 2 percent). Other substances used included nicotine, alcohol, and non-opioid psychoactive drugs (primarily cannabis). Oxycodone was the most frequently reported opioid of abuse.
Recreational opioid users have distinct drug-related behaviors and preferences. Monitoring current trends and examining these behaviors is an important component to understand the potential safety risks associated with recreational opioid use.
Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in ...patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential.
This was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test—Revised, and the Digit–Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed.
Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking Emax (P < 0.0001) compared with those receiving placebo, confirming study validity. Compared with placebo, Drug-Liking was not significantly different for subjects taking 750-mg CBD (P = 0.51). Drug-Liking Emax values for 1500-mg and 4500-mg CBD were significantly different from placebo (P = 0.04 and 0.002, respectively); however, the mean differences were <10 points on VAS compared with >18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported.
Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.
•Therapeutic cannabidiol dose shows low abuse potential in polydrug users.•Feel good effects of cannabidiol significantly lower than alprazolam and dronabinol•Cannabidiol administration shows no observable cognitive/psychomotor effects.•Majority of adverse events were of mild and moderate severity.•No serious adverse events or deaths reported during the trial
Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent ...formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.
Rationale
Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of ...insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health.
Objectives
This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act.
Results
LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks.
Conclusions
LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.
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