Alvimopan

<0.1 mg/mL

White to light beige powder. Solubility: <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0; 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. /Alvimpoan dihydrate/

8.34e-03 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Zwitterion at physiological pH /Alvimpoan dihydrate/

Crystals; mp: 210-213 °C. Specific optical rotation = +51.8 deg at 25 °C/D (c = 1.0 in DMSO) /Alvimopan dihydrate/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 35 reports by companies from 1 notifications to the ECHA C&L Inventory.

Warning

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl alvimopan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Drug Name: Entereg; FDA Application No.: (NDA) 021775; Active Ingredient: Alvimopan; Company: Cubist Pharms; Original Approval or Tentative Approval Date: May 20, 2008; Chemical Type: 1 New molecular entity (NME); Review Classification: Standard review drug.

Acute Tox. 4 (100%)

Skin Irrit. 2 (100%)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Alvimopan competitively binds to mu-opioid receptor in the gastrointestinal tract but, unlike methylnaltrexone which relies upon it ionic charge, alvimopan owes its selectivity for peripheral receptors to its pharmacokinetics. Alvimopan binds to peripheral mu-receptors with a Ki of 0.2 ng/mL.

Alvimopan is a selective antagonist of the cloned human mu-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of (3)H-alvimopan from the human mu-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 uM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels.

Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract mu-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations where alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of mu-opioid agonists.

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity.