Naloxegol

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Naloxegol
Clinical data
Trade namesMovantik, Moventig
Other namesNKTR-118
AHFS/Drugs.commovantik
License data
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
  • (5α,6α)-4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propen-1-yl)morphinan-3,14-diol
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)
  • COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@]2([C@H]3Cc4ccc(c5c4[C@]2([C@H]1O5)CCN3CC=C)O)O
  • InChI=1S/C34H53NO11/c1-3-9-35-10-8-33-30-26-4-5-27(36)31(30)46-32(33)28(6-7-34(33,37)29(35)25-26)45-24-23-44-22-21-43-20-19-42-18-17-41-16-15-40-14-13-39-12-11-38-2/h3-5,28-29,32,36-37H,1,6-25H2,2H3/t28-,29+,32-,33-,34+/m0/s1
  • Key:XNKCCCKFOQNXKV-ZRSCBOBOSA-N

Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherally selective opioid 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]

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]

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.[8] 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.

also

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. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  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. {{cite news}}: Unknown parameter |dead-url= ignored (|url-status= suggested) (help)
  4. ^ "Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation". Aliment. Pharmacol. Ther. 40: 771–9. Oct 2014. doi:10.1111/apt.12899. PMID 25112584.
  5. ^ a b 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.
  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. {{cite web}}: Unknown parameter |dead-url= ignored (|url-status= suggested) (help)
  7. ^ Movantik Prescribing information. AstraZeneca. 2017 https://www.azpicentral.com/movantik/movantik.pdf#page=1
  8. ^ 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. {{cite book}}: Unknown parameter |dead-url= ignored (|url-status= suggested) (help)


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