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.
As the area under the curve 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 proteins, mainly to albumin.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 to naldemedine 3-glucuronide. Minor metabolites are the 6-glucuronide, the 7-(R/S)-hydroxy-derivates, and two products formed by enterobacteria through cleaving the oxadiazole 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. 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 is about 11 hours. Chemistry
Naldemedine is used in form of the tosylate, a white to light tan powder. It is not hygroscopic and has a high water solubility at a physiologic pH.