| Systematic (IUPAC) name | |
|---|---|
| 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3-phenylpropanoyl]amino)acetic acid | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a608051 |
| Licence data | US FDA:link |
| Pregnancy cat. | ? |
| Legal status | ? |
| Routes | Oral |
| Identifiers | |
| CAS number | 156053-89-3 |
| ATC code | A06AH02 |
| PubChem | CID 5488548 |
| DrugBank | DB06274 |
| ChemSpider | 4589864 |
| UNII | Q153V49P3Z |
| ChEMBL | CHEMBL270190 |
| Synonyms | Alvimopan, Entereg |
| Chemical data | |
| Formula | C25H32N2O4 |
| Mol. mass | 424.53 g/mol |
| SMILES | eMolecules & PubChem |
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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 withdrawals.[1][2] The Food and Drug Administration reviewed the safety and efficacy data for alvimopan and approved its use in May 2008.[3]
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Alvimopan is indicated in patients 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.[4]
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.[4]
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%. [4]
80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.[4]
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.[4]
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.[4]
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. The drug is a 12 mg blue hard gelatin capsule. The recommended adult dose is to administer 12 mg 30 minutes to 5 hours preoperatively and 12 mg twice daily for seven days postoperatively. A patient should receive no more than 15 doses.[4]
The most common side effects associated with alvimopan are:[1]
| 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 |
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 expect 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.[4]
During clinical trials, a 12 month study of alvimopan dosed at 0.5 mg twice daily reported observed more myocardial infarction in the treatment group compared to placebo. The majority of these events occurred between months one and four of treatment. No causal relationship between alvimopan and myocardial infarction was ever established, and this effect has not been reproduced in subsequent studies.
During clinical trials, one patient with severe hepatic impairment appreciated a 10-fold increase in Cmax compared to healthy volunteers. Two other patients with a similar Child-Pugh score (class C) did not experience this same phenomenon.
Alvimopan has not been studied in patients with end-stage renal disease.
It is not recommended to use alvimopan in surgical candidates for correction of a complete bowel obstruction.
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, cyclosporine, itraconazole, quinine, quinidine, spironolactone, and verapamil.[4]
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