Naloxegol

Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherally acting μ-opioid receptor antagonist developed by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation.[2] It was approved in 2014 in adult patients with chronic, non-cancer pain.[3] Doses of 25 mg were found safe and well tolerated for 52 weeks.[4] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[5]

Naloxegol
Clinical data
Trade namesMovantik, Moventig
Other namesNKTR-118
AHFS/Drugs.commovantik
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding~4.2%
    MetabolismHepatic (CYP3A)
    Elimination half-life6–11 h
    ExcretionFeces (68%), urine (16%)
    Identifiers
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    KEGG
    ChEBI
    CompTox Dashboard (EPA)
    Chemical and physical data
    FormulaC34H53NO11
    Molar mass651.785 g/mol g·mol−1
    3D model (JSmol)

    The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting and headache. As a pure opioid antagonist Naloxegol has no potential for abuse.

    Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids, but was recently reclassified as a prescription drug after the FDA concluded that the impermeability of the blood-brain barrier to this compound made it non-habit-forming, and so without the potential for abuse—specifically, naloxegol was officially decontrolled on 23 January 2015.[6]

    Medical use

    Naloxegol is indicated for the treatment of opioid-induced constipation (OIC) in patients with chronic non-cancer pain. It is recommended that any maintenance laxative be discontinued before starting naloxegol or be held for at-least 3 days. Naloxegol should be taken on an empty stomach at least two hours after the last meal.[7]

    Pharmacodynamic properties

    Naloxegol inhibits opioid binding in μ-opioid receptors in the gastrointestinal tract, thus decreasing the constipating effects (slowing of gastrointestinal motility and transit, hypertonicity, increased fluid reabsorption) associated with opioids.[8]

    If naloxegol is coadministered with other opioid antagonists, there is a potential for additive effect and increased risk of opioid withdrawal.[7]

    Mechanism of action

    Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 6-α-hydroxyl group of α-naloxol is connected via an ether linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The "n=7" defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the "monomethoxy" indicates that the terminal hydroxyl group of the PEG is "capped" with a methyl group.[9] The pegylation of the 6-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood-brain barrier (BBB).[5] As such, it can be considered the antithesis of the peripherally-acting opiate loperamide which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.

    See also
    • Alvimopan (trade name Entereg)
    • Methylnaltrexone (trade name Relistor)
    • Naldemedine (trade name Symproic)
    • (+)-Naloxone - a non-opioid drug which also reduces some side effects of opioids without significantly affecting analgesia when used in small oral doses
    • 6β-Naltrexol (6α-hydroxynaltrexone) - an investigational medication

    References and notes
    1. Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi; Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 14 May 2012.
    2. "Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119". Archived from the original on 2012-02-13. Retrieved 2012-05-14.
    3. "FDA approves MOVANTIK™ (naloxegol) Tablets C-II for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain". 16 September 2014. Archived from the original on 2015-05-10.
    4. Webster, L.; Chey, W. D.; Tack, J.; Lappalainen, J.; Diva, U.; Sostek, M. (Oct 2014). "Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation" (PDF). Aliment. Pharmacol. Ther. 40 (7): 771–9. doi:10.1111/apt.12899. PMID 25112584.
    5. Garnock-Jones KP (2015). "Naloxegol: a review of its use in patients with opioid-induced constipation". Drugs. 75 (4): 419–425. doi:10.1007/s40265-015-0357-2. PMID 25666542.
    6. "Schedules of Controlled Substances: Removal of Naloxegol From Control". www.deadiversion.usdoj.gov. Archived from the original on 2016-03-09. Retrieved 2016-02-27.
    7. "Movantik prescribing information highlights". AstraZeneca. Retrieved 2019-08-14.
    8. Garnock-Jones, Karly P. (2015-03-01). "Naloxegol: A Review of Its Use in Patients with Opioid-Induced Constipation". Drugs. 75 (4): 419–425. doi:10.1007/s40265-015-0357-2. ISSN 1179-1950.
    9. Technically, the molecule that is attached via the ether link is O-methyl-heptaethylene glycol [that is, methoxyheptaethylene glycol, CH3OCH2CH2O(CH2CH2O)5CH2CH2OH], molecular weight 340.4, CAS number 4437-01-8. See Pubchem Staff (2016). "Compound Summary for CID 526555, Pubchem Compound 4437-01". PubChem Compound Database. Bethesda, MD, USA: NCBI, U.S. NLM. Archived from the original on 2016-02-05. Retrieved 28 January 2016.
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