Naloxegol

Naloxegol
Clinical data
Trade names Movantik, Moventig
AHFS/Drugs.com movantik
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code A06AH03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding ~4.2%
Metabolism Hepatic (CYP3A)
Biological half-life 6–11 h
Excretion Feces (68%), urine (16%)
Identifiers
Synonyms NKTR-118
CAS Number 854601-70-0
PubChem (CID) 56959087
ChemSpider 28651656
ChEBI CHEBI:82975
Chemical and physical data
Formula C34H53NO11
Molar mass 651.785 g/mol
3D model (Jmol) Interactive image

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]

Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 5-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.[6] The pegylation of the 5-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.

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. [7]

As an opiate antagonist, it is not expected to be capable of inducing the euphoria and anxiolytic effects which are generally cited as the desirable effects of commonly abused opiates (all of which are opiate agonists) if it were to cross the BBB; it would in fact reverse the effects of opiate drugs of abuse if it entered the central nervous system.

See 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". 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.
  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. 1 2 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. ↑ 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. Retrieved 28 January 2016.
  7. ↑ http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0123_3.htm


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