Alvimopan: Difference between revisions

{{Short description|Chemical compound}}

| verifiedrevid = 456683046

| image = Alvimopan2DCSD.svg

| image2 = Alvimopan3DanJ.gif

| width2 = 250px

| tradename = Entereg

| pregnancy_US = B

| legal_US = Rx-only

| bioavailability = 6%

| protein_bound = 80% (parent drug), 94% (metabolite)

| metabolism = Gut microflora-mediated hydrolysis to active metabolite

| elimination_half-life = 10-17 hours

| excretion = Faeces, urine (35%)

| IUPHAR_ligand = 7471

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 156053-89-3

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| UNII = Q153V49P3Z

| ChEMBL_Ref = {{ebicite|correct|EBI}}

'''Alvimopan''' (trade name '''Entereg''') is a [[drug]] which behaves as a [[peripherally acting μ-opioid receptor antagonist]]. With the limited ability to cross the [[blood–brain barrier]] and reach the [[μ-opioid receptor]]s 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]].<ref name="neary_2005">{{cite journal | vauthors = Neary P, Delaney CP | title = Alvimopan | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 4 | pages = 479–488 | date = April 2005 | pmid = 15882122 | doi = 10.1517/13543784.14.4.479 | s2cid = 219293329 }}</ref><ref>{{cite journal | vauthors = Schmidt WK | title = Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist | journal = American Journal of Surgery | volume = 182 | issue = 5A Suppl | pages = 27S–38S | date = November 2001 | pmid = 11755894 | doi = 10.1016/S0002-9610(01)00784-X }}</ref> It is currently only [[Food and Drug Administration]] approved for the treatment of postoperative [[ileus]] which it received in May 2008.<ref>[https://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html FDA press release - FDA Approves Entereg to Help Restore Bowel Function Following Surgery]</ref><ref>{{cite journal | vauthors = Sharma A, Jamal MM | title = Opioid induced bowel disease: a twenty-first century physicians' dilemma. Considering pathophysiology and treatment strategies | journal = Current Gastroenterology Reports | volume = 15 | issue = 7 | pages = 334 | date = July 2013 | pmid = 23836088 | doi = 10.1007/s11894-013-0334-4 | s2cid = 32265790 }}</ref>

== 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.<ref name="label">Alvimopan Product Label as approved by the FDA on May 20, 2008.</ref>

== Adverse effects ==

There is a potential risk of [[myocardial infarction]] in patients using alvimopan long-term.<ref>{{Cite web|title=HIGHLIGHTS OF PRESCRIBING INFORMATION|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021775s010lbl.pdf|url-status=live|archive-url=https://web.archive.org/web/20150908182049/http://www.accessdata.fda.gov:80/drugsatfda_docs/label/2013/021775s010lbl.pdf |archive-date=2015-09-08 }}</ref><ref>{{cite journal | vauthors = Erowele GI | title = Alvimopan (Entereg), a Peripherally Acting mu-Opioid Receptor Antagonist For Postoperative Ileus | journal = P & T | volume = 33 | issue = 10 | pages = 574–583 | date = October 2008 | pmid = 19750041 | pmc = 2730789 }}</ref>

! Frequency (%) with alvimopan

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.<ref name="label" />

== 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]].<ref name="label" />

== Pharmacology ==

=== Mechanism of action ===

Alvimopan is a [[Competitive inhibition|competitive]] [[Receptor antagonist|antagonist]] of the [[Μ-opioid receptor|μ-opioid receptors]] (MOR) in the gastrointestinal tract, with a Ki of 0.2&nbsp;ng/mL. Activation of these receptors by endogenous or exogenous [[agonist]]s reduces gastrointestinal motility, and alvimopan blocks this effect. Like most other peripherally-selective MOR antagonists, such as [[Naloxegol|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|blood-brain barrier]] and affect the central nervous system.<ref>{{cite journal | vauthors = Streicher JM, Bilsky EJ | title = Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications | journal = Journal of Pharmacy Practice | volume = 31 | issue = 6 | pages = 658–669 | date = December 2018 | pmid = 28946783 | pmc = 6291905 | doi = 10.1177/0897190017732263 }}</ref><ref name="label" />

=== 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%.<ref name="label" />

==== Distribution ====

80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.<ref name="label" />

==== 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.<ref name="label" />

==== 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.<ref name="label" />

== Dosing and administration ==

Alvimopan is required by the FDA to participate in [[Risk Evaluation and Mitigation Strategies|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.<ref name="label" />

== See also ==

* [[Axelopran]]

* [[Bevenopran]]

* [[LY-88329]]

* [[Methylnaltrexone]]

* [[Naldemedine]]

* [[Naloxegol]]

{{Opioid receptor modulators}}

[[Category:4-Phenylpiperidines]]

[[Category:Carboxamides]]

[[Category:Mu-opioid receptor antagonists]]

[[Category:Peripherally selective drugs]]

[[Category:Drugs developed by GSK plc]]

[[Category:Drugs developed by Merck & Co.]]