Zolpidem

Zolpidem

1.0          Introduction

Hypnotic agents and sedatives have been around for centuries; zolpidem being just the latest development to emerge as the result of a drug discovery program that aimed to improve upon the existing benzodiazepine compounds, which include psychoactive drugs such as diazepam. While benzodiazepines possess sedative and hypnotic actions which have since marketed these drugs as excellent muscle relaxants and anti-anxiety medications, high dosages and long-term prescriptions of these compounds facilitated decreasing effectiveness, physical dependence, and extreme withdrawal. Therefore, in the early 1990s, a drug discovery program sought to identify a new, non-benzodiazepine compound that would facilitate a rapid, but temporary sedative effect by binding to the same benzodiazepine receptors so that it might produce the similar effects drugs such as diazepam could produce without resulting in the same addictive effects. [1] In order to accomplish this, the research program synthesized different ligands that would attach to the benzodiazepine receptors in the same way diazepam and other benzodiazepine compounds could. [1] While many imidazopyridine compounds had affinities for the receptor sites, one such derivative, zolpidem, was selected during the in vitrostudies based on its extremely high affinity for the benzodiazepine receptors in the cerebellum and hippocampus regions of the brain. [1]

2.0          History

The first form of zolpidem was developed by a French multinational pharmaceutical company, now known as Sanofi Aventis.Sanofi Aventis is a French pharmaceutical company that formed in 2004 as the result of a merger of Aventis and Sanofi Synthelabo, which were each the products of additional company mergers. [2] As the fifth largest pharmaceutical company in the world in prescription sales, Sanofi Aventis currently manufacturers over fifty different prescription medications that address a wide range of conditions. Sanofi Aventis also funds several research development programs to develop new molecular compounds as well as new formulations for existing compounds. A product of one such development program was zolpidem tartrate in 1988. [2] 

Zolpidem was approved for medical use in the United States in 1992.[1] Sanofi Aventis received two patents for Ambien, which was their brand name of the zolpidem tartrate compound. It became available as a generic medicine in 2007 when the company’s patent on the compound expired.[3] 

2.1           Commercialization

Zolpidem was first introduced in the United States as “Ambien,” which was the brand name given to the drug by the owning company Sanofi Aventis. [4] In 1988, the company applied for two US patents for a new molecular compound manufactured at two different prescription strengths. On December 16, 1992, the company received two US patents for immediate release (IR) zolpidem formulation, branded as Ambien, at both the 5 mg and 10 mg prescription strength tablet. [4] Both patents were filed under the same New Drug Application (NDA) 019908. [4]

Ambien was protected by both patents on the market for fifteen years, during which Sanofi Aventis was the sole manufacturer of the brand name drug. However, on April 21, 2007, the company’s patents for zolpidem tartrate expired, allowing the FDA to grant generic patents on zolpidem tartrate. [4] As of 2018, there were thirteen manufacturers who still retain generic patents on zolpidem tartrate tablets. These include: Mylan Pharmaceuticals, TEVA Pharmaceuticals USA, Roxane Laboratories, Watson Laboratories, Ranbaxy Laboratories, Dr. Reddy’s Laboratories, Apotex, Synthon Pharmaceuticals, Genpharm, Mutual Pharmaceutical Company, Caraco Pharmaceutical Laboratories, Carlsbad Technology, and Lek Pharmaceuticals. [5]

2.2        Intellectual Property

In the late 1980s, Sanofi Aventis funded a drug discovery program with the objective of identifying and developing a non-benzodiazepine compound which would demonstrate rapid onset, but short-duration sedative effects by binding to the same GABA_Areceptors that other known benzodiazepine compounds are able to bind to.[1] The research program resulted in the identification of imidazopyridine derivatives and eventually to the development of zolpidem tartrate formulations. [1]

In December of 1992, Sanofi Aventis was granted two US patents under the same NDA 019908 for their zolpidem tartrate tablets, branded as Ambien, at both the 5 mg and 10 mg strength tablets. For fifteen years, Ambien was protected under these two US patents, and Sanofi Aventis was the sole intellectual owner of the immediate release zolpidem tartrate formulation. [4] When both US patents expired on April 21, 2007, the immediate release zolpidem formulation became a generic prescription; however, Sanofi Aventis still retains a US patent on its controlled release (CR) zolpidem formulation; however, this patent will also expire on December 1, 2019. [4]

2.3         Cost

With the protection of both US patents, Sanofi Aventis marketed its immediate release (IR) zolpidem tartrate tablets as the brand “Ambien” which sold at around $488 for a one month’s supply. [6] Since the expiration of its patents, Sanofi Aventis now sells its immediate release (IR) formulation of zolpidem tartrate tablets at around $8 for a one month’s supply in order to compete with the many generic formulations now available. [6] Sanofi Aventis still retains an active patent on their controlled release formulation of zolpidem tartrate tablets, and therefore is able to sell this medication at around $68 per one month’s supply. [3]

In the second quarter of the fiscal year in 2007, profits rapidly fell for Sanofi Aventis, partially due to the expiration of its two US patents on the immediate release (IR) form of Ambien. Second quarter profits for the combined sales of Ambien (IR), Ambien (CR), and Stilnox fell 41.8% in 2007 in global sales to approximately 287 million dollars. [7] In this United States, Ambien (IR) sales fell even more to 62.0%. [8]

3.0       Mechanism of Action

The basic chemical mechanism which facilitates the soporific effect of both benzodiazepine compounds like diazepam and non-benzodiazepine compounds like zolpidem is as a gamma-aminobutyric acid (GABA_A) agonist. [9] This involves both types of compounds attacking the same neurotransmitters in the brain and allosterically binding to the GABA_Areceptors. [10] Essentially, by stimulating these neurotransmitters, both diazepam and zolpidem inhibit brain function and activity thereby producing the sedative and hypnotic effect in patients. However, further studies which analyzed the mechanism of zolpidem as a non-benzodiazepine sedative discovered acute differences in the binding of the benzodiazepine receptors. While both zolpidem and drugs such as diazepam have similar affinities for the benzodiazepine GABA_Areceptors on these neurotransmitters, the benzodiazepine compounds share an equal affinity for each of the GABA_Areceptors containing either the α₁, α₂, α₃ or α₅ subunits. Zolpidem, however, possesses a unique affinity for only one of these specific receptors: the GABA_Areceptor containing the α₁ subunit. [9] It is this extreme selectivity which makes zolpidem the most desirable agent not only as a marketed hypnotic agent, but also as a subject for research concerning the GABA_Areceptors in the brain. 

4.0       Pharmacology 

Zolpidem has an absolute bioavailability of about 70% and is rapidly absorbed in the gastrointestinal tract after oral administration [11].  Zolpidem concentrations in the plasma peak around 1.5 hours after administration before the compound in eliminated by the liver. [11]  While zolpidem has high bioavailability, it has  a short half-life of only 2.5 to 3 hours.

Zolpidem is metabolized by way of hydroxylation to inactive metabolites in the liver primarily by CYP3A4 but also by CYP1A2 and CYP2D6. [1] There are no active metabolites. The inactive metabolites are eliminated renally, primarily through the urine.[11]

5.0       Prescription Use

Zolpidem has been marketed as a prescription medication primarily for the ephemeral treatment of insomnia. It is fast-acting with a half-life of only three hours; zolpidem is therefore extremely successful in initiating sleep. [14] While drugs like diazepam were prescribed for both short-term and long-term treatment of insomnia, zolpidem does not possess long-term soporific effects, which greatly reduces the addictive aspects that are prominent and problematic in benzodiazepine compounds like diazepam. As reported in the CNS Drug Reviews, “The Pharmacology and Mechanism of Action of Zolpidem”, several studies repeatedly reported fewer withdrawal symptoms for zolpidem than diazepam even when administered at higher dosages. [1] This suggests that even at higher dosages of zolpidem, little tolerance or physical dependence develops. In fact, a study reported by British Journal of Pharmacologyhas proposed a possible link between zolpidem’s unique therapeutic effects and zolpidem’s unique selectivity concerning the GABA_Areceptors. The study found that the sedative effect of zolpidem was found to be mediated by the α₁-GABA_Areceptor up to doses of at least 60 mg/kg based on the failure of zolpidem to reduce motor activity in theα₁subject group. [11] These findings have since marketed zolpidem as the safer and more effective short-term hypnotic therapy to replace benzodiazepine compounds such as diazepam. While zolpidem still carries several other adverse effects such as headache, nausea, amnesia, and anxiety, these adverse effects are found in minor, isolated occurrences. [14] 

Ambien remains the most prescribed medication out of all hypnotic agents, being prescribed four times more often than the leading competitor. [12] Ambien currently averages approximately 40 million prescriptions annually and continues to be prescribed now as a cheap generic, costing only $2 per pill. [12]However, prescriptions for all hypnotic agents declined from 57 million tablets in 2013 to 47 million in 2017, probably due to the rising concern of prescribing medications with addictive properties amidst the opioid crisis in the United States. [3]

As of 2018, zolpidem tartrate tablets were marketed under all of the following brands: Adorma, Adorma, Albapax, Ambien, Atrimon, Belbien, Bikalm, Cymerion, Dactive, Dalparan, Damixan, Dormeben, Dormilam, Dormilan, Eanox, Edluar, Edluar, Flazinil, Fulsadem, Hypnogen, Hypnonorm, Intermezzo, Inzofresh, Ivadal, Ivedal, Le Tan, Lioram, Lunata, Medploz, Mondeal, Myslee, Nasen, Nocte, Nottem, Noxidem, Noxizol, Nuo Bin, Nytamel, Nyxe, Olpitric, Onirex, Opsycon, Polsen, Sanval, Semi-Nax, Sleepman, Somex, Somidem, Somit, Somnil, Somnipax, Somnipron, Somno, Somnogen, Somnor, Sonirem, Sove, Soza, Stilnoct, Stilnox, Stilpidem, Stimin, Sublinox, Sucedal, Sumenan, Vicknox, Viradex, Xentic, Zasan, Zaviana, Ziohex, Zipsoon, Zodem, Zodenox, Zodium, Zodorm, Zolcent, Zoldem, Zoldorm, Zoldox, Zolep, Zolfresh, Zolip, Zolman, Zolmia, Zolnox, Zolnoxs, Zolodorm, Zolpeduar, Zolpel, Zolpi, Zolpi-Q, Zolpic, Zolpidem, Zolpidem tartrate, Zolpidemi tartras, Zolpidemtartraat, Zolpidemtartrat, Zolpidemum, Zolpigen, Zolpihexal, Zolpimist, Zolpineo, Zolpinox, Zolpirest, Zolpistar, Zolpitop, Zolpitrac, Zolpium, Zolprem, Zolsana, Zolta, Zoltar, Zolway, Zomnia, Zonadin, Zonoct, Zopid, Zopidem, Zopim, and Zorimin. [15]

6.0       Regulation

Along with benzodiazepine compounds, zolpidem is classified as a Schedule IV substance in the Umited States according to the Controlled Substances Act. [3] As a Schedule IV substance, zolpidem has a relatively low potential for abuse; however, abuse of the drug could lead to physical dependence or psychological dependence.

Zolpidem tartrate is classified as a Category C medication for women who are pregnant or may become pregnant. [12] There is no established research on the effect zolpidem tartrate immediate release (IR) and controlled release tablets may have on a pregnancy. [12]

No active recalls have been issued by the FDA concerning zolpidem tartrate tablets since its introduction into US market in 1992. However, in 2013 the FDA issued a recommendation that the dose be lowered for female patients. This was the result of several studies which concluded that the clearance of zolpidem was gender dependent. [16] Zolpidem is eliminated through the renal system more slowly in women than in men; therefore, the same dose given to female patients results in greater drug exposure and greater AUC. [12] However, in geriatric patients, the elimination of zolpidem is the same for both men and women and therefore the dosage of zolpidem does not depend on gender. [12]

7.0       Research

In 2017, a review in JAMA Neurology established that there is evidence of zolpidem’s efficacy on treating other disorders of consciousness other than insomnia, such as vegetative states. [17] However, the study also concluded that more research would be needed to study such effects.

Most recently, researchers at the University of Notre Dame published research on the application of zolpidem to treat tuberculosis. The study found zolpidem to have antituberculosis activity when screened against replicating Mycobacterium tuberculosis. The researchers synthesized Zolpidem anagrams and analogues to investigate their antitubercular potency against mycobacteria and Gram-positive and Gram-negative bacteria.[18] The manipulation of zolpidem’s structural isomers were found to vastly improve the potency against drug-resistant Mycobacterium tuberculosis strains.[18]

8.0       Conclusion

Its selectivity of GABA_Areceptors and its efficacy as a rapid but brief sedative separate zolpidem as a much safer and more reliable hypnotic drug when compared to diazepam and other benzodiazepine compounds like it. In an age where addiction is unpredictable and unrelenting, drug discovery research programs, such as the one which produced zolpidem, should always consider the unexpected effects of chemical mechanisms which repeatedly target biological receptors. Zolpidem is an excellent example, not only of a product of drug discovery and development, but also of continuing drug discovery and development, since zolpidem remains an important experimental tool for neuropharmacological research. [1] Until more selective compounds are discovered and synthesized, zolpidem will remain an important drug for both the prescription treatment of insomnia and for the research and development of improved medicines to replace it for the treatment of insomnia.

9.0       References

1.    Sanger, D., & Depoortere H. (1998). “The Pharmacology and Mechanism of Action of Zolpidem”. CNS Drug Reviews 4(4), 323-340. doi: 10.1111/j.1527-3458.1998.tb00074.x

2.    “Sanofi, a global biopharmaceutical company focused on human health”. https://www.sanofi.com/ (accessed Oct 22, 2018).

3.    “Zolpidem”. https://en.wikipedia.org/wiki/Zolpidem (accessed Oct 26, 2018).

4.    “Drugs@FDA: FDA Approved Drug Products”. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019908 (accessed Oct 18, 2018).

5.    Hitti, M. “FDA OKs 1st Generic Versions of Ambien”. https://www.webmd.com/sleep-disorders/news/20070423/fda-oks-generic-ambien (accessed Oct 18, 2018).

6.    Matheson E, Hainer BL (2017). "Insomnia: Pharmacologic Therapy". American Family Physician. 96 (1): 29–35. Retrieved from https://www.aafp.org/afp/2017/0701/p29.html(accessed Oct 25, 2018).

7.    “Sanofi-Aventis 2nd-qtr profit falls as generics take toll on Eloxati and Ambien” (2007). https://www.thepharmaletter.com/article/sanofi-aventis-2nd-qtr-profit-falls-as-generics-take-toll-on-eloxati-and-ambien (accessed Oct 26, 2018).

8.    Espinoza, J. “Generics Wound Sanofi” (2008). https://www.forbes.com/2008/04/30/sanofi-drug-pill-markets-equities-cx_je_0430markets26.html (accessed Oct 26, 2018).

9.    Elliot, E., & White, J. (2001). “The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry”. Neuropharmacology, 40 (5), 717-721. https://doi.org/10.1016/S0028-3908(00)00196-9

10.  Wright, Brittany T. (http://orcid.org/0000-0002-1501-6596), "Repeated Zolpidem Treatment Effects on Sedative Tolerance, Withdrawal, mRNA Levels, and Protein Expression" (2016). Theses and Dissertations(ETD). Paper 406. http://dx.doi.org/10.21007/ etd.cghs.2016.0408 (accessed Oct 19, 2018).

11.  Crestani, F., Martin, J., Mohler, H., & Rudolph, U. (2000). “Mechanism of action of the hypnotic zolpidem vivo”. British Journal Of Pharmacology, 131(7), 1251-1254. https://doi.org/10.1038/sj.bjp.0703717(accessed Oct 25, 2018).

12.  Drugs.com. (2018). Zolpidem Tartrate Monograph for Professionals - Drugs.com. [online] Retrieved from https://www.drugs.com/monograph/zolpidem-tartrate.html (accessed 22 Oct. 2018).

13.  Krasowski, M., & Brown, J. (2018). “Zolpidem (Ambien): An Introduction for Professionals – Concordia University, St. Paul Online”. Retrieved from https://online.csp.edu/blog/forensic-scholars-today/introduction-to-ambien(accessed Oct 20, 2018).

14.  Zolpidem. (2018). Retrieved from http://pubchem.ncbi.nlm.nih.gov/compound/zolpidem(accessed Oct 20, 2018).

15.  "International brands for zolpidem". Drugs.com. Retrieved 15 March 2018. Retrieved from https://www.drugs.com/international/zolpidem.html(accessed Oct 20, 2018).

16.  "FDA Requires Lower Dosing of Zolpidem". The Medical Letter on Drugs and Therapeutics. The Medical Letter. 55 (1408): 5. January 21, 2013. Retrieved from https://secure.medicalletter.org/article-share?a=1408a&p=tml&title=FDA%20Requires%20Lower%20Dosing%20of%20Zolpidem&cannotaccesstitle=1(accessed Oct 20 2018).

17.  Bomalaski MN, Claflin ES, Townsend W, Peterson MD (2017). “Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review”. JAMA Neurology. 74 (9): 1130-1139. doi: 10.1001/jamaneurol.2017.1133(accessed Oct 25, 2018).

18.  Moraski, G.; Miller, P.; Bailey, M.; Ollinger, J.; Parish, T.; Boshoff, H.; Cho, S.; Anderson, J.; Mulugeta, S.; Franzblau, S. et al. “Putting Tuberculosis (TB) To Rest: Transformation Of The Sleep Aid, Ambien, And “Anagrams” Generated Potent Antituberculosis Agents”. ACS Infectious Diseases 2015, 1, 85-90.doi: 10.1021/id500008t (accessed Oct 26, 2018).