Naloxegol

Naloxegol
Clinical data
Trade namesMovantik, Moventig
Other namesNKTR-118
AHFS/Drugs.commovantik
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding~4.2%
MetabolismLiver (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 mass651.794 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;[4] 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.[5] It was approved in 2014 in adult patients with chronic, non-cancer pain.[6] Doses of 25 mg were found safe and well tolerated for 52 weeks.[7] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[8]

The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache.[9]

Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids. It was officially decontrolled in January 2015. It was reclassified as a prescription drug after the FDA and DEA concluded that the impermeability of the blood–brain barrier to this compound made it non-habit-forming, and so without the potential for abuse.[10]

Medical use

Naloxegol is indicated for the treatment of opioid-induced constipation (OIC) in people with chronic non-cancer pain.[9][11]

Side effects

The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache.[9]

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.[12]

If naloxegol is coadministered with other opioid antagonists, there is a potential for additive effect and increased risk of opioid withdrawal.[9]

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.[13] The pegylation of the 6-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood–brain barrier (BBB).[8]

References

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ^ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada. 4 May 2016. Retrieved 7 April 2024.
  3. ^ "Moventig EPAR". European Medicines Agency (EMA). 8 December 2014. Retrieved 28 September 2024.
  4. ^ Seifert R, Wieland T, Mannhold R, Kubinyi H, Folkers G (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.
  5. ^ "Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119". Archived from the original on 13 February 2012. Retrieved 14 May 2012.
  6. ^ "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 10 May 2015.
  7. ^ Webster L, Chey WD, Tack J, Lappalainen J, Diva U, Sostek M (October 2014). "Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation" (PDF). Alimentary Pharmacology & Therapeutics. 40 (7): 771–9. doi:10.1111/apt.12899. PMID 25112584. S2CID 34286557.
  8. ^ a b Garnock-Jones KP (March 2015). "Naloxegol: a review of its use in patients with opioid-induced constipation". Drugs. 75 (4): 419–25. doi:10.1007/s40265-015-0357-2. PMID 25666542. S2CID 207488539.
  9. ^ a b c d "Movantik prescribing information highlights" (PDF). Retrieved 14 August 2019.
  10. ^ "Schedules of Controlled Substances: Removal of Naloxegol From Control". www.deadiversion.usdoj.gov. Archived from the original on 9 March 2016. Retrieved 27 February 2016.
  11. ^ "Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain" (PDF).
  12. ^ Garnock-Jones KP (March 2015). "Naloxegol: a review of its use in patients with opioid-induced constipation". Drugs. 75 (4): 419–25. doi:10.1007/s40265-015-0357-2. PMID 25666542. S2CID 207488539.
  13. ^ 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 "Compound Summary for CID 526555, Pubchem Compound 4437-01". PubChem Compound Database. Bethesda, MD: NCBI, U.S. NLM. 2016. Archived from the original on 5 February 2016. Retrieved 28 January 2016.

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