|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||301.474 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor. The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, but it is a weak inhibitor of CYP2D6. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects.
Deramciclane was discovered by EGIS Pharmaceuticals Ltd in Budapest, Hungary. In 2000, EGIS signed over exclusive rights to Orion Pharma to further develop, register, and market deramciclane. Successful pre-clinical, Phase I, and Phase II trials looked promising to the company and its investors even up until the third quarter of 2002. Phase I studies show little to no side effects of deramciclane. Phase II studies show little to no side effects and statistically significant improvement on the Hamilton Anxiety Rating Scale in response to daily 60 mg doses, but not in response to daily 10 or 30 mg doses. Finally, in February, 2003, deramciclane development for use against general anxiety disorder (GAD) was discontinued during Phase III trials due to clinically insignificant results compared to placebo groups.
Pharmacokinetics of deramciclane
There have been several clinical studies to examine the pharmacokinetics of deramciclane, which can readily cross the blood-brain barrier. Overall, studies show that deramciclane follows linear pharmacokinetics in humans with oral daily doses ranging from 3–150 mg and twice daily doses ranging from 10–60 mg. Additionally, no differences have been found in adsorption, distribution, metabolism, or elimination when an oral dose is administered in tablet or capsule form.
Deramciclane is rapidly absorbed from the gastrointestinal tract. Studies show that the drug can be detected in plasma as quickly as 20 minutes after dosing. Deramciclane demonstrates a Tmax of 2–4 hours and is unaffected by dosage. The Cmax at this time is approximately 140 ng/mL. A typical PTF (peak trough fluctuation) is 70-80% over four weeks of administration, and is unaffected by dose. The oral tablet of deramciclane yields a bioavailability of 36% on average, which is considered decent enough for oral administration and avoid the necessity of a more invasive route.
The pharmacokinetics of deramciclane are also studied in rats, mice, rabbits, and dogs. Rat and rabbits show the fastest metabolism rates of the drug, and dogs are the only animals to show non-linear pharmacokinetics of deramciclane. Phase I metabolism in rat hepatocytes is similar enough to that in humans that the rat can be used as a predictive model for human metabolism of deramciclane. In rats, the Tmax is found to be 0.5 hours after a single 10 mg/kg dose and the half-life of deramciclane is about 3.5-5.5 hours. As expected, deramciclane reaches greatest peak plasma concentrations with intravenous administration, followed by intraperitoneal, then oral administration with the lowest peak plasma concentration.
Studies assessing the elimination half-life of deramciclane point to a range of 20–32 hours for T1/2. The elimination half-life appears to increase with dosage. There is some evidence for accumulation of deramciclane, though it is a topic of debate.
It is important to understand the metabolism pathway of a drug to better understand its pharmacology, toxicity, and animal model predictability. The metabolism pathway in humans is not entirely clear, though certain reactions have been shown to happen in the breakdown of deramciclane. For example, deramciclane undergoes side chain modification and oxidation at multiple positions on the molecule. The side chain reaction forms phenylborneol and N-desmethyl deramciclane which is the active metabolite of deramciclane. Oxidation of the molecule results in many hydroxy-, carboxy-, and N-oxide derivatives.
Also important to the pharmacokinetics of a drug is its interactions with food during adsorption because this affects the dosage required. Deramciclane is an acid-labile compound. Acid-labile compounds are more easily broken down in acidic environments, so the decrease in stomach pH as a result of the presence of food could have adverse effects on the bioavailability of deramciclane. Clinical studies investigating the effects of food or lack thereof on deramciclane adsorption show that there is a statistically significant, but not clinically relevant, increase in bioavailability of deramciclane when administered with food because the point of critical instability of deramciclane is relatively low at a pH of 2. The presence of food does not affect deramciclane's elimination half-life (T1/2) or mean residence time (MRT).
Safety and side effects
All clinical studies have shown that deramciclane is well tolerated in humans at dosages ranging between 0.2–150 mg. All reported side effects were mild-moderate with the most common side effect being headache and dizziness. No severe side effects were reported in any clinical trial, and no side effects were found to be dose-dependent. Trial participants showed no significant increases in liver enzyme activity and no changes in ECGs, systolic blood pressure, diastolic blood pressure, HDL cholesterol, or LDL cholesterol levels. Another advantage to deramciclane is that it did not produce any withdrawal effects after long-term studies, like other anxiolytics do.
- Tiagabine, another GABA reuptake inhibitor
- Orion Pharma Inlicenses Deramciclane from Egis Pharmaceuticals. Phase 3 Program in Anxiety has Started, 2000 http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=29979
- Kanerva H, Vilkman H, Någren K, Kilkku O, Kuoppamäki M, Syvälahti E, Hietala J (July 1999). "Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study". Psychopharmacology. 145 (1): 76–81. doi:10.1007/s002130051034. PMID 10445375. S2CID 20661122.
- Pälvimäki EP, Majasuo H, Kuoppamäki M, Männistö PT, Syvälahti E, Hietala J (March 1998). "Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation". Psychopharmacology. 136 (2): 99–104. doi:10.1007/s002130050544. PMID 9551765. S2CID 33983579.
- Kovács I, Maksay G, Simonyi M (March 1989). "Inhibition of high-affinity synaptosomal uptake of gamma-aminobutyric acid by a bicyclo-heptane derivative". Arzneimittel-Forschung. 39 (3): 295–7. PMID 2502985.
- Celada P, Puig M, Amargós-Bosch M, Adell A, Artigas F (July 2004). "The therapeutic role of 5-HT1A and 5-HT2A receptors in depression". Journal of Psychiatry & Neuroscience. 29 (4): 252–65. PMC 446220. PMID 15309042.
- Laine K, Ahokoski O, Huupponen R, Hänninen J, Palovaara S, Ruuskanen J, et al. (December 2003). "Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone". European Journal of Clinical Pharmacology. 59 (10): 761–6. doi:10.1007/s00228-003-0674-3. PMID 14566442. S2CID 38235268.
- Laine K, De Bruyn S, Björklund H, Rouru J, Hänninen J, Scheinin H, Anttila M (February 2004). "Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics". European Journal of Clinical Pharmacology. 59 (12): 893–8. doi:10.1007/s00228-003-0714-z. PMID 14730412. S2CID 21409667.
- Huupponen R, Anttila M, Rouru J, Kanerva H, Miettinen T, Scheinin M (August 2004). "Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers". International Journal of Clinical Pharmacology and Therapeutics. 42 (8): 449–55. doi:10.5414/cpp42449. PMID 15366325.
- Monostory K, Kohalmy K, Ludányi K, Czira G, Holly S, Vereczkey L, et al. (November 2005). "Biotransformation of deramciclane in primary hepatocytes of rat, mouse, rabbit, dog, and human". Drug Metabolism and Disposition. 33 (11): 1708–16. doi:10.1124/dmd.105.003764. PMID 16118331. S2CID 6551928.
- Naukkarinen H, Raassina R, Penttinen J, Ahokas A, Jokinen R, Koponen H, et al. (December 2005). "Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study". European Neuropsychopharmacology. 15 (6): 617–23. doi:10.1016/j.euroneuro.2005.03.002. PMID 15949921. S2CID 8514329.
- Blow to Orion as deramciclane fails in Phase III anxiety studies, 2003 http://www.thepharmaletter.com/article/blow-to-orion-as-deramciclane-fails-in-phase-iii-anxiety-studies
- Drabant S, Nemes KB, Horváth V, Tolokán A, Grézal G, Anttila M, et al. (November 2004). "Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers". European Journal of Pharmaceutics and Biopharmaceutics. 58 (3): 689–95. doi:10.1016/j.ejpb.2004.03.036. PMID 15451546.
- Kanerva H, Kilkku O, Heinonen E, Helminen A, Rouru J, Tarpila S, et al. (October 1999). "The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers". Biopharmaceutics & Drug Disposition. 20 (7): 327–34. doi:10.1002/(SICI)1099-081X(199910)20:7<327::AID-BDD192>3.0.CO;2-8. PMID 10760840.
- Kanerva H, Kilkku O, Helminen A, Rouru J, Scheinin M, Huupponen R, et al. (December 1999). "Pharmacokinetics and safety of deramciclane during multiple oral dosing". International Journal of Clinical Pharmacology and Therapeutics. 37 (12): 589–97. PMID 10599951.
- Kertész S, Kapus G, Gacsályi I, Lévay G (February 2010). "Deramciclane improves object recognition in rats: potential role of NMDA receptors". Pharmacology, Biochemistry, and Behavior. 94 (4): 570–4. doi:10.1016/j.pbb.2009.11.012. PMID 19963003. S2CID 27014927.
- Huupponen R, Paija O, Salonen M, Björklund H, Rouru J, Anttila M (2003). "Pharmacokinetics of deramciclane, a novel anxiolytic agent, after intravenous and oral administration". Drugs in R&D. 4 (6): 339–45. doi:10.2165/00126839-200304060-00002. PMID 14584962. S2CID 25819561.
- Nemes KB, Abermann M, Bojti E, Grézal G, Al-Behaisi S, Klebovich I (January 2000). "Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat". The Journal of Pharmacy and Pharmacology. 52 (1): 47–51. doi:10.1211/0022357001773670. PMID 10716602. S2CID 40494609.
- Foley FW, Traugott U, LaRocca NG, Smith CR, Perlman KR, Caruso LS, Scheinberg LC (March 1992). "A prospective study of depression and immune dysregulation in multiple sclerosis". Archives of Neurology. 49 (3): 238–44. doi:10.1001/archneur.1992.00530270052018. PMID 1536625.