Naloxegol

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]

Naloxegol

Clinical data
Trade names	Movantik, Moventig
Other names	NKTR-118
AHFS/Drugs.com	movantik
License data	US DailyMed: Naloxegol
Routes of administration	By mouth
ATC code	A06AH03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only[2] US: ℞-only EU: Rx only[3]
Pharmacokinetic data
Protein binding	~4.2%
Metabolism	Liver (CYP3A)
Elimination half-life	6–11 h
Excretion	Feces (68%), urine (16%)
Identifiers
IUPAC name (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	854601-70-0
PubChem CID	56959087
ChemSpider	28651656
UNII	44T7335BKE
KEGG	D10479
ChEBI	CHEBI:82975
CompTox Dashboard (EPA)	DTXSID80234684
Chemical and physical data
Formula	C34H53NO11
Molar mass	651.794 g·mol−1
3D model (JSmol)	Interactive image
SMILES COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@]2([C@H]3Cc4ccc(c5c4[C@]2([C@H]1O5)CCN3CC=C)O)O
InChI 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

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]