Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

-induced

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

in adults with chronic non-cancer pain. It is a

peripherally acting μ-opioid receptor antagonist Peripherally acting μ-opioid receptor antagonists (PAMORAs) are a class of chemical compounds that are used to reverse adverse effects caused by opioids interacting with receptors outside the central nervous system (CNS), mainly those located in ...

and was developed by

Shionogi is a Japanese pharmaceutical company best known for developing Crestor. Medical supply and brand name also uses katakana (シオノギ). Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines prod ...

. Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderate

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

side effects. Effects indicative of central

opioid withdrawal Opioid withdrawal is a set of symptoms (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...

or impact on the analgesic or

miotic Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...

effects of co-administered opioids have only been observed in a small number of patients.

Medical uses

In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation. on Symproic. In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a

laxative Laxatives, purgatives, or aperients are substances that loosen stools and increase bowel movements. They are used to treat and prevent constipation. Laxatives vary as to how they work and the side effects they may have. Certain stimulant, lubri ...

Contraindications

The drug is contraindicated in patients with gastrointestinal obstruction or

perforation A perforation is a small hole in a thin material or web. There is usually more than one perforation in an organized fashion, where all of the holes collectively are called a ''perforation''. The process of creating perforations is called perfor ...

, or those at risk for these problems.

Side effects

Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

, depending on the study), diarrhea (7% versus 2–3%),

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

(4–6% versus 2–5%), vomiting (3% versus 2%), gastroenteritis (2–3% versus 1%), and

opioid withdrawal syndrome Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Op ...

(1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate.

Hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

reactions were rare; they occurred in two patients.

Overdose

Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate.

Interactions

As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...

(which increased naldemedine exposure 2.9-fold in a study), ketoconazole,

clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...

and

grapefruit juice Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...

. Conversely, CYP3A4 inducers such as rifampicin and

St John's wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus '' Hypericum''. Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found ...

decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study. Strong inhibitors of the pump P-glycoprotein such as

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

may increase naldemedine concentrations in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

Pharmacology

Mechanism of action

Naldemedine is a derivative of

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been foun ...

and, like this substance, blocks

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin ...

s of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat

opioid dependence Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Op ...

, the large

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are ...

side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs.

Pharmacokinetics

After oral intake, naldemedine has an absolute

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal. As the

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

is not significantly different with or without a meal, the drug can be taken independently of food. Once in the bloodstream, 93 to 94% of the substance is bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s, mainly to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine (which makes up about 9–13% of the circulating substance), and to a much lesser extent by

UGT1A3 UDP-glucuronosyltransferase 1-3 is an enzyme that in humans is encoded by the ''UGT1A3'' gene. This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, ...

to naldemedine 3-

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

. Minor metabolites are the 6-glucuronide, the 7-( R/S)- hydroxy-derivates, and two products formed by

enterobacteria Enterobacteriaceae is a large family of Gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their ...

through cleaving the

oxadiazole Oxadiazoles are a class of heterocyclic aromatic chemical compound of the azole family; with the molecular formula C2H2N2O. There are four isomers of oxadiazole: File:1,2,3-oxadiazole.svg, 1,2,3-oxadiazole File:1,2,4-oxadiazole.svg, 1,2,4-oxadiazo ...

ring: naldemedine carboxylic acid and benzamidine. Nor-naldemedine, the glucuronides, and the carboxylic acid are opioid receptor antagonists, but less potent than the original substance. File:Nor-naldemedine skeletal.svg, Nor-naldemedine, the main metabolite File:Naldemedine metabolism.svg, Minor metabolites: blue are

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

sites, brown is the hydroxylation site, and green the cleavage site Naldemedine and its metabolites are excreted via urine and faeces. The part of the molecule "left" of the cleavage line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and ''carboxylic acid'') is found to 20.4% in the urine and to 64.3% in the faeces, while the part "right" to the line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and ''benzamidine'') is found to 57.3% in the urine and to 34.8% in the faeces. This indicates that benzamidine is predominantly excreted in the urine and the carboxylic acid is predominantly excreted in the faeces. The

terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is about 11 hours.

Chemistry

Naldemedine is used in form of the

tosylate In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a tolyl group, –, joined to a sulfonyl group, ––, with the open valence on s ...

, a white to light tan powder. It is not

hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...

and has a high water solubility at a physiologic pH.

Society and culture

Commercialization

Naldemedine is manufactured by Shionogi Inc., a United States-based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a pharmaceutical company founded in 1878 based in

Osaka, Japan is a designated city in the Kansai region of Honshu in Japan. It is the capital of and most populous city in Osaka Prefecture, and the third most populous city in Japan, following Special wards of Tokyo and Yokohama. With a population of 2.7 ...

. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States. In the US market, Shionogi Inc. has partnered with

Purdue Pharma Purdue Pharma L.P., formerly the Purdue Frederick Company, is an American privately held pharmaceutical company founded by John Purdue Gray. It was owned principally by members of the Sackler family as descendants of Mortimer and Raymond Sackl ...

in a joint venture for US commercialization of Symproic. Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders. Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017. The

Drug Enforcement Administration The Drug Enforcement Administration (DEA; ) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within the U.S. It is the lead agency for domestic en ...

officially removed the Class II scheduling in September 2017.

Manufacturer finances

Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000. How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.

Intellectual property

There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026 to 2031. Naldemedine tosylate has 46 other patents in 18 different countries.

Clinical trials

The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries. COMPOSE-II began in November 2013 until June 2015 taking place in 69 outpatient clinics in six countries. In both trials, patients were randomly assigned to receive either naldemedine 0.2 mg or placebo once daily for 12 weeks. A responder had at least three spontaneous bowel movements per week with an increase of one spontaneous bowel movement for nine of the 12 weeks, including three of the final four weeks of the study. In COMPOSE-I and COMPOSE-II, the proportion of responders were significantly higher in the naldemedine group than the placebo group. Adverse events were similar in both trials, however, patients in the naldemedine group had slightly higher rates of adverse events. COMPOSE-III was a 52-week clinical trial examining the long term safety with naldemedine in patients with non cancer chronic pain. Results from this trial showed statistical significance for increased weekly bowel movements and no opioid withdrawal symptoms. The study also concluded adverse effects were more similar between two groups. All trials were conducted following Good Clinical Practice guidelines.

References

External links

* {{Portal bar , Medicine Carboxamides Cyclopropanes 4,5-Epoxymorphinans Mu-opioid receptor antagonists Oxadiazoles Peripherally selective drugs