Alvimopan

Alvimopan

Systematic (IUPAC) name
2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3-phenylpropanoyl]amino)acetic acid
Clinical data
Trade names	Entereg
AHFS/Drugs.com	monograph
MedlinePlus	a608051
Licence data	US FDA:link
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	6%
Protein binding	80% (parent drug), 94% (metabolite)
Metabolism	Gut microflora-mediated hydrolysis to active metabolite
Biological half-life	10-17 hours
Excretion	Faeces, urine (35%)
Identifiers
CAS Number	156053-89-3 N
ATC code	A06AH02 (WHO)
PubChem	CID: 5488548
IUPHAR/BPS	7471
DrugBank	DB06274 Y
ChemSpider	4589864 Y
UNII	Q153V49P3Z N
ChEMBL	CHEMBL270190 Y
Synonyms	Alvimopan, Entereg
Chemical data
Formula	C25H32N2O4
Molecular mass	424.53 g/mol
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
NY (what is this?)  (verify)

Alvimopan (trade name Entereg) is a drug which behaves as a peripherally acting μ-opioid antagonist. With limited ability to cross the blood–brain barrier, many of the undesirable side-effects of the opioid agonists such as constipation are minimized without affecting analgesia or precipitating withdrawal. It is currently only Food and Drug Administration approved for the treatment of postoperative ileus 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.

Adverse effects

The most common side effects associated with alvimopan are:

Adverse Effect	Frequency (%) with placebo	Frequency (%) with alvimpoan
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 mu-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 substrate for the cytochrome P450 enzyme system. Therefore, no interactions are expected with hepatically metabolized drugs. Alvimopan is substrate for p-glycoprotein. Expect interactions with known p-glycoprotein inhibitors such as amiodarone, depridil, diltiazem, ciclosporin, itraconazole, quinine, quinidine, spironolactone, and verapamil.

Pharmacology

Mechanism of action

Alvimopan competitively binds to mu-opioid receptor in the gastrointestinal tract. Unlike methylnaltrexone (another peripherally acting mu-receptor antagonist) that bears a quaternary amine, alvimopan owes its selectivity for peripheral receptors to its kinetics. Alvimopan binds to peripheral mu-receptors with a Ki of 0.2 ng/mL and dissociates slower than most other ligands.

Pharmacokinetics

Absorption

Peak plasma concentration (Cmax) of alvimopan is reached approximately 2 hours after oral dosing, while the Cmax for metabolite occurs 36 hours after an oral dose. Alvimopan's high affinity for the peripheral mu-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 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.

See also

• Axelopran
• Bevenopran
• Methylnaltrexone
• Naldemedine
• Naloxegol