Alvimopan

Alvimopan
Names
Trade namesEntereg
Other namesAlvimopan, 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 classPeripherally acting μ-opioid receptor antagonist[1]
Main usesIleus after partial bowel resection[2]
Side effectsHeart burn, heart attack[2]
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Pregnancy
category
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth
    Typical dose12 mg BID[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa608051
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability6%
    Protein binding80% (parent drug), 94% (metabolite)
    MetabolismGut microflora-mediated hydrolysis to active metabolite
    Elimination half-life10-17 hours
    ExcretionFaeces, urine (35%)
    Chemical and physical data
    FormulaC25H32N2O4
    Molar mass424.541 g·mol−1
    3D model (JSmol)
    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 checkY
    • Key:UPNUIXSCZBYVBB-JVFUWBCBSA-N checkY

    Alvimopan, sold under the brand name Entereg, is a medication used to speed recovery from ileus after partial bowel resection with surgical anastomosis.[2] It may be used after either small bowel or large bowel surgery.[1] It is taken by mouth.[1]

    Common side effects include heart burn.[2] Other side effects may include a heart attack and low potassium.[2][1] Safety in pregnancy is unclear.[3] It is a peripherally acting μ-opioid receptor antagonist.[1]

    Alvimopan was approved for medical use in the United States in 2008.[2] In the United States 15 doses of 12 mg costs about 2,900 USD as of 2022.[4]

    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.[5]

    Dosage

    It is given as 12 mg 20 minutes to 5 hours before surgery.[2] Further doses of 12 mg twice a day starting the day after surgery may be used for up to 7 days.[2]

    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.[5]

    Side effects

    The most common side effects associated with alvimopan are:[6]

    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.[5]

    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.[5]

    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.[6][7]

    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.[8][5]

    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 μ-receptor results in an absolute bioavailability less than 7%.[5]

    Distribution

    80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.[5]

    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.[5]

    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.[5]

    References

    1. 1 2 3 4 5 "Alvimopan Monograph for Professionals". Drugs.com. Archived from the original on 28 June 2021. Retrieved 14 January 2022.
    2. 1 2 3 4 5 6 7 8 9 "DailyMed - ALVIMOPAN capsule". dailymed.nlm.nih.gov. Archived from the original on 19 April 2021. Retrieved 14 January 2022.
    3. ↑ "Alvimopan (Entereg) Use During Pregnancy". Drugs.com. Archived from the original on 3 December 2020. Retrieved 14 January 2022.
    4. ↑ "Entereg Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 14 January 2022.
    5. 1 2 3 4 5 6 7 8 9 Alvimopan Product Label as approved by the FDA on May 20, 2008.
    6. 1 2 Neary P, Delaney CP (April 2005). "Alvimopan". Expert Opinion on Investigational Drugs. 14 (4): 479–88. doi:10.1517/13543784.14.4.479. PMID 15882122. S2CID 219293329.
    7. ↑ Schmidt WK (November 2001). "Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist". American Journal of Surgery. 182 (5A Suppl): 27S–38S. doi:10.1016/S0002-9610(01)00784-X. PMID 11755894.
    8. ↑ Streicher, John M.; Bilsky, Edward J. (December 2018). "Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications". Journal of Pharmacy Practice. 31 (6): 658–669. doi:10.1177/0897190017732263. PMC 6291905. PMID 28946783.
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