Alvimopan

Alvimopan

Names
Trade names	Entereg
Other names	Alvimopan, Entereg
IUPAC name 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3-phenylpropanoyl]amino)acetic acid
Clinical data
Drug class	Peripherally acting μ-opioid receptor antagonist
Main uses	Ileus after partial bowel resection
Side effects	Heart burn, heart attack
Pregnancy category	US: B (No risk in non-human studies)
Routes of use	By mouth
Typical dose	12 mg BID
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a608051
Legal
License data	US FDA: Alvimopan
Legal status	US: ℞-only
Pharmacokinetics
Bioavailability	6%
Protein binding	80% (parent drug), 94% (metabolite)
Metabolism	Gut microflora-mediated hydrolysis to active metabolite
Elimination half-life	10-17 hours
Excretion	Faeces, urine (35%)
Chemical and physical data
Formula	C25H32N2O4
Molar mass	424.541 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(O)CNC(=O)[C@@H](Cc1ccccc1)CN3CC[C@@](c2cccc(O)c2)([C@H](C3)C)C
InChI InChI=1S/C25H32N2O4/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30)/t18-,20-,25+/m0/s1 Y Key:UPNUIXSCZBYVBB-JVFUWBCBSA-N Y

Alvimopan, sold under the brand name Entereg, is a medication used to speed recovery from ileus after partial bowel resection with surgical anastomosis. It may be used after either small bowel or large bowel surgery. It is taken by mouth.

Common side effects include heart burn. Other side effects may include a heart attack and low potassium. Safety in pregnancy is unclear. It is a peripherally acting μ-opioid receptor antagonist.

Alvimopan was approved for medical use in the United States in 2008. In the United States 15 doses of 12 mg costs about 2,900 USD as of 2022.

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.

Dosage

It is given as 12 mg 20 minutes to 5 hours before surgery. Further doses of 12 mg twice a day starting the day after surgery may be used for up to 7 days.

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.

Side effects

The most common side effects associated with alvimopan are:

Adverse Effect	Frequency (%) with placebo	Frequency (%) with alvimopan
Dyspepsia	4.6	7.0
Hypokalemia	8.5	9.5
Back Pain	1.7	3.3
Delayed Micturition	2.1	3.2

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 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, bepridil, diltiazem, ciclosporin, itraconazole, quinine, quinidine, spironolactone, and verapamil.

Pharmacology

Mechanism of action

With the limited ability to cross the blood–brain barrier and reach the μ-opioid receptors of the central nervous system, the clinically undesirable effects of centrally acting opioid antagonists (like reversal of opioid-mediated analgesia) are avoided without affecting the intended blockade of μ-opioid receptors in the gastrointestinal tract.

Alvimopan is a competitive antagonist of the μ-opiod 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, 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.

External links

Identifiers:	ATC code: A06AH02 (WHO) CAS Number: 156053-89-3 N PubChem CID: 5488548 IUPHAR/BPS: 7471 DrugBank: DB06274 Y ChemSpider: 4589864 Y UNII: Q153V49P3Z ChEMBL: ChEMBL270190 Y