Influence of mild and moderate liver impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist

Shakeri‐Nejad, Kasra; Hoch, Matthias; Hoever, Petra; Dingemanse, Jasper

doi:10.1016/j.ejps.2013.06.002

Cited by 4 publications

(2 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been predicted to interact with both receptors' transmembrane domains 3 and 5-7, the same domains predicted to be the site of endogenous ligand binding [61]. Although its development was discontinued in 2011 by Actelion and GlaxoSmithKline due to effects on liver enzyme parameters [62][63][64], it continues to be used in research and medicinal chemists are continuing to develop substituted tetrahydroisoquinolines to produce selective OX 1 receptor antagonists [65]. GlaxoSmithKline's SB-649868 is a piperidine but its carboxamide benzofuran group is instrumental for its activity [66].…”

Section: Synthetic Orexin Ligandsmentioning

confidence: 99%

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

View full text Add to dashboard Cite

Addiction is a chronic relapsing disorder which presents a significant global health burden and unmet medical need. The orexin/hypocretin system is an attractive potential therapeutic target as demonstrated by the successful clinical trials of antagonist medications like Suvorexant for insomnia. It is composed of two neuropeptides, orexin-A and orexin-B and two excitatory and promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have a variety of functions, most notably in regulating arousal, appetite and reward. The orexins have been shown to have a role in mediating the effects of several drugs of abuse, such as cocaine, morphine and alcohol via projections to key brain regions such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. However, it has not yet been demonstrated whether the dual orexin receptor antagonists (DORAs) under development for insomnia are ideal drugs for the treatment of addiction. The question of whether to use a DORA or single orexin receptor antagonist (SORA) for the treatment of addiction is a key question that will need to be answered in order to maximize the clinical utility of orexin receptor antagonists. This review will examine the role of the orexin/hypocretin system in addiction, orexin-based pharmacotherapies under development and factors affecting the selection of one or both orexin receptors as drug targets for the treatment of addiction.

show abstract

Section: Synthetic Orexin Ligandsmentioning

confidence: 99%

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

View full text Add to dashboard Cite

show abstract

“…Female subjects were required to use a reliable method of contraception from screening until 30 days after the last study drug administration. Participating subjects had to be non-smokers and given that almorexant is a substrate of cytochrome P450 3A4,17 consumption of grapefruit and grapefruit juice was forbidden from screening until the end-of-study examination. The latter took place after the last blood sample for pharmacokinetics was withdrawn, ie, 120 hours after the last study drug administration in treatment period 3 (study II) or 4 (study I).…”

Section: Methodsmentioning

confidence: 99%

Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies

Dingemanse¹,

Géhin²,

Cruz³

et al. 2014

DDDT

Self Cite

View full text Add to dashboard Cite

Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API) was sticking to the apparatus used during tablet compression; almorexant has an absolute bioavailability of 11.2%; and almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old “sticky” tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet but with a larger API crystal size and a tablet with 30% more excipients as well as a larger API crystal size. This latter formulation was available in two strengths. The geometric mean ratios and 90% confidence interval of the area under the curve (AUC) were within the bioequivalence range of 0.80–1.25 for the different comparisons between formulations. In study II, 100 mg of the reference tablet was compared to 25 and 50 mg of a liquid-filled hard gelatin capsule developed to increase the bioavailability of almorexant. The geometric mean ratios of the maximum concentration and AUC comparing the new 25 and 50 mg capsule formulations to the reference tablet did not exceed 0.25 and 0.50, respectively, indicating that the new capsule formulation did not increase the maximum concentration of or the total exposure to almorexant. In conclusion, a new tablet was developed but formulation development aimed at increasing the bioavailability of almorexant failed.

show abstract

Drug Discovery in Erectile Dysfunction and Sleep Disorders

Rotella

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

show abstract

Influence of mild and moderate liver impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist

Cited by 4 publications

References 26 publications

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies

Drug Discovery in Erectile Dysfunction and Sleep Disorders

Contact Info

Product

Resources

About