Drug repositioning
Encyclopedia
Drug repositioning is the application of known drugs
and compounds to new indications (i.e., new diseases).
and pharmaceutical companies
see their drug pipelines drying up and realize that many previously promising technologies have failed to deliver ‘as advertised’.
Using drug repositioning, pharmaceutical companies have achieved a number successes, for example Pfizer
's Viagra in erectile dysfunction
and Celgene
's thalidomide
in severe erythema nodosum leprosum. Smaller companies, including Ore Phamaceuticals, Biovista
, Numedicus and Melior Discovery
are also performing drug repositioning on a systematic basis. These companies use a combination of approaches including in silico biology and in vivo/in vitro experimentation to assess a compound and develop and confirm hypotheses concerning its usage for new indications.
A significant advantage of drug repositioning over traditional drug development
is that since the repositioned drug has already passed a significant number of toxicity
and other tests, its safety is known and the risk of failure for reasons of adverse toxicology are reduced. More than 90% of drugs fail during development, and this is the most significant reason for the high costs of pharmaceutical R&D. In addition, repurposed drugs can bypass much of the early cost and time needed to bring a drug to market. On the other hand drug repositioning faces some challenges itself since the intellectual property issues surrounding the original drug may be complex and from a commercial point of view it may not always make sense to take such a drug to market.
One notable example of drug repurposing is taking the partial mu-opioid receptor agonist buprenorphine
- which has been prescribed for control of moderate pain for decades in low dosages in the form of Temgesic 200mcg sublingual tablets, Buprenex 300mcg/mL ampoules - and marketing a high-dosage formulation (Subutex 2 mg and 8 mg) for the interruption and maintenance of heroin and other opioid
addictions, which it has proven very beneficial for, with over 200,000 people in the United States alone on buprenorphine maintenance. Some of the reasons for this are that the drug has a ceiling effect - higher doses do not cause further activation of opioid receptors - and a very long half-life
in >2 mg dosages. It also has an extremely high binding affinity for opioid receptors, which keeps the drug from being displaced by opioids like Dilaudid, heroin, morphine
, and oxycodone
, with the result that a user maintained on it can not get high no matter what dosage taken of most opioids. The only opioids that may be able to break through the buprenorphine blockade (which are required in an acute-care setting if a buprenorphine patient requires pain relief, as no standard opioids are strong enough) - drugs with similar or higher binding affinities to buprenorphine itself - are the fentanil-class opioids, and the Bentley-series opioids (cf. etorphine
, dihydroetorphine
), which are rarely primary drugs of abuse and not often found on the streets. Buprenorphine itself is a modified Bentley-series opioid.
Requip is another notable example of drug repurposing. Originally developed as an anti-Parkinsonian agent, it has found application in the treatment of both Restless Legs Syndrome and SSRI-induced sexual dysfunction.
Colesevelam
is another example of drug repurposing. Originally developed as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia as monotherapy, it has also gained approval to improve glycemic control in adults with type 2 diabetes mellitus.
Another example of drug repurposing is that of gabapentin
, and its chemical cousin pregabalin
. Originally developed as anti-epileptics, they have found more use treating anxiety
disorders and neuropathic pain than as seizure medications.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
and compounds to new indications (i.e., new diseases).
Drug repositioning
Drug repositioning has been growing in importance in the last few years as an increasing number of drug developmentDrug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
and pharmaceutical companies
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
see their drug pipelines drying up and realize that many previously promising technologies have failed to deliver ‘as advertised’.
Using drug repositioning, pharmaceutical companies have achieved a number successes, for example Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
's Viagra in erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and Celgene
Celgene
Celgene Corporation is a manufacturer of drug therapies for cancer and inflammatory disorders. It is incorporated in Delaware and headquartered in Summit, New Jersey...
's thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
in severe erythema nodosum leprosum. Smaller companies, including Ore Phamaceuticals, Biovista
Biovista
Biovista Inc. is a private drug development services company based in Charlottesville, Virginia, USA. Biovista's core business activities include Drug repositioning and drug de-risking as well as disease cohort analysis, adverse event prediction and clinical hold analysis services...
, Numedicus and Melior Discovery
Melior Discovery
Melior Discovery, Inc. is a private biopharmaceutical company based in Exton, Pennsylvania, USA. The company specializes in drug repositioning and has established a technology it uses for this purpose. According to the company’s website, Melior also offers certain contract research...
are also performing drug repositioning on a systematic basis. These companies use a combination of approaches including in silico biology and in vivo/in vitro experimentation to assess a compound and develop and confirm hypotheses concerning its usage for new indications.
A significant advantage of drug repositioning over traditional drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
is that since the repositioned drug has already passed a significant number of toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
and other tests, its safety is known and the risk of failure for reasons of adverse toxicology are reduced. More than 90% of drugs fail during development, and this is the most significant reason for the high costs of pharmaceutical R&D. In addition, repurposed drugs can bypass much of the early cost and time needed to bring a drug to market. On the other hand drug repositioning faces some challenges itself since the intellectual property issues surrounding the original drug may be complex and from a commercial point of view it may not always make sense to take such a drug to market.
One notable example of drug repurposing is taking the partial mu-opioid receptor agonist buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
- which has been prescribed for control of moderate pain for decades in low dosages in the form of Temgesic 200mcg sublingual tablets, Buprenex 300mcg/mL ampoules - and marketing a high-dosage formulation (Subutex 2 mg and 8 mg) for the interruption and maintenance of heroin and other opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
addictions, which it has proven very beneficial for, with over 200,000 people in the United States alone on buprenorphine maintenance. Some of the reasons for this are that the drug has a ceiling effect - higher doses do not cause further activation of opioid receptors - and a very long half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
in >2 mg dosages. It also has an extremely high binding affinity for opioid receptors, which keeps the drug from being displaced by opioids like Dilaudid, heroin, morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, and oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
, with the result that a user maintained on it can not get high no matter what dosage taken of most opioids. The only opioids that may be able to break through the buprenorphine blockade (which are required in an acute-care setting if a buprenorphine patient requires pain relief, as no standard opioids are strong enough) - drugs with similar or higher binding affinities to buprenorphine itself - are the fentanil-class opioids, and the Bentley-series opioids (cf. etorphine
Etorphine
Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver...
, dihydroetorphine
Dihydroetorphine
Dihydroetorphine was developed by K.W.Bentley at McFarlan-Smith in the 1960s and is a potent analgesic drug , which is used mainly in China...
), which are rarely primary drugs of abuse and not often found on the streets. Buprenorphine itself is a modified Bentley-series opioid.
Requip is another notable example of drug repurposing. Originally developed as an anti-Parkinsonian agent, it has found application in the treatment of both Restless Legs Syndrome and SSRI-induced sexual dysfunction.
Colesevelam
Colesevelam
Colesevelam is a bile acid sequestrant administered orally. It is developed by Genzyme and marketed in the US by Daiichi Sankyo under the brand name WelChol and elsewhere by Genzyme under the tradename Cholestagel.-Clinical use:...
is another example of drug repurposing. Originally developed as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia as monotherapy, it has also gained approval to improve glycemic control in adults with type 2 diabetes mellitus.
Another example of drug repurposing is that of gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, and its chemical cousin pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
. Originally developed as anti-epileptics, they have found more use treating anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
disorders and neuropathic pain than as seizure medications.