Alvimopan (trade name Entereg) is a drug which behaves as 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 ...

. With the limited ability to cross the blood–brain barrier and reach the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

s of 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 ...

, the clinically undesirable effects of centrally acting

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 ...

antagonists (like reversal of opioid-mediated analgesia) are avoided without affecting the intended blockade of μ-opioid receptors in the gastrointestinal tract. It is currently only

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

approved for the treatment of postoperative

ileus Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' is from Ancient Greek ''eileós'' (, "intestinal obstruction"). The term 'subileus' ref ...

which it received in May 2008.

Medical uses

Alvimopan is indicated in people to avoid postoperative ileus following partial large or small bowel resection with primary anastomosis. Alvimopan accelerates the gastrointestinal recovery period as defined by time to first bowel movement or flatus.Alvimopan Product Label as approved by the FDA on May 20, 2008.

Adverse effects

There is a potential risk of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

in patients using alvimopan long-term. The most common side effects associated with alvimopan are:

Contraindications

Alvimopan is absolutely contraindicated in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately prior to when alvimopan would be initiated because individuals with recent exposure to opioids are expected to be more sensitive to the effects of μ-opioid receptor antagonists. The peripheral site of action of alvimopan suggests that such a heightened sensitivity would precipitate gastrointestinal effects beyond dyspepsia.

Interactions

Alvimopan is not a substrate for the

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzyme system. Therefore, no interactions are expected with hepatically metabolized drugs. Alvimopan is substrate for P-glycoprotein. Thus, interactions are to be expected with known P-glycoprotein inhibitors such as

amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibril ...

bepridil Bepridil (trade name Vascor) is an diamine calcium channel blocker once used to treat angina pectoris. It is no longer sold in the United States. It is nonselective. It has been discussed as a possible option in the treatment of atrial fibrilla ...

, diltiazem,

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 ...

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 ...

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...

quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is the enantiomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood press ...

, and

verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be ...

Pharmacology

Mechanism of action

Alvimopan is a

competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indivi ...

antagonist of the μ-opioid receptors (MOR) in the gastrointestinal tract, with a Ki of 0.2 ng/mL. Activation of these receptors by endogenous or exogenous agonists reduces gastrointestinal motility, and alvimopan blocks this effect. Like most other peripherally-selective MOR antagonists, such as naloxegel and

methylnaltrexone Methylnaltrexone (MNTX, brand name Relistor), used in form of methylnaltrexone bromide (INN, USAN, BAN), is a medication that acts as a peripherally acting μ-opioid receptor antagonist that acts to reverse some of the side effects of opioid dr ...

, alvimopan is selective for peripheral receptors because is effluxed by P-glycoprotein, which reduces its ability to cross the blood-brain barrier and affect the central nervous system.

Pharmacokinetics

Absorption

Peak plasma concentration (C_max) of alvimopan is reached approximately 2 hours after oral dosing, while the C_max for metabolite occurs 36 hours after an oral dose. Alvimopan's high affinity for the peripheral μ-receptor results in an absolute bioavailability less than 7%.

Distribution

80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.

Metabolism

Alvimopan undergoes no significant hepatic metabolism, but is metabolized by intestinal flora. Gut metabolism produces an active metabolite with no clinically significant contribution to drug effect.

Elimination

Alvimopan undergoes 35% renal excretion and greater than 50% biliary excretion. Drug metabolized by intestinal flora is excreted in the feces. Alvimopan's half-life of elimination is 10 to 17 hours, while that of the gut metabolite is 10 to 18 hours.

Dosing and administration

Alvimopan is required by the FDA to participate in Risk Evaluation and Mitigation Strategy (REMS) to ensure safe use. Alvimopan is only approved for short term use of no more than 15 doses. It is available on an inpatient basis at institutions approved by and registered with the Entereg Access Support and Education (E.A.S.E.) program. A person should receive no more than 15 doses.

References

{{Opioid receptor modulators Phenols 4-Phenylpiperidines Carboxamides Acetic acids Mu-opioid receptor antagonists Peripherally selective drugs GSK plc brands Merck & Co. brands