Identification

Name
Naloxegol
Accession Number
DB09049
Type
Small Molecule
Groups
Approved
Description

Naloxegol, for "PEGylated naloxol" is a peripherally-selective opioid antagonist developed by AstraZeneca. It was approved by the FDA in September 2014 and is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non‑cancer pain. The advantage of naloxegol over the opioid antagonist naloxone is that its PEGylated structure allows for high selectivity for peripheral opioid receptors and lack of entry into the central nervous system through the blood-brain barrier.

Structure
Thumb
Synonyms
  • (5α,6α)-17-Allyl-6-[(20-hydroxy-3,6,9,12,15,18-hexaoxaicos-1-yl)oxy]-4,5-epoxymorphinan-3,14-diol
External IDs
AZ-13337019 / NKTR-118
Product Ingredients
IngredientUNIICASInChI Key
Naloxegol oxalate65I14TNM331354744-91-4MNYIRXLCPODKLG-VUTNLTPYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MovantikTablet, film coated12.5 mg/1OralAstra Zeneca Lp2015-03-06Not applicableUs
MovantikTablet25 mgOralKnight Therapeutics Inc.2015-08-27Not applicableCanada
MovantikTablet, film coated25 mg/1OralAvera McKennan Hospital2016-03-222018-06-11Us
MovantikTablet12.5 mgOralKnight Therapeutics Inc.2015-08-27Not applicableCanada
MovantikTablet, film coated25 mg/1OralAstra Zeneca Lp2015-03-06Not applicableUs
MovantikTablet, film coated25 mg/1OralLake Erie Medical Dba Quality Care Produts Llc2015-03-06Not applicableUs
MoventigTablet, film coated25 mgOralKyowa Kirin Limited2014-12-08Not applicableEu
MoventigTablet, film coated12.5 mgOralKyowa Kirin Limited2014-12-08Not applicableEu
MoventigTablet, film coated25 mgOralKyowa Kirin Limited2014-12-08Not applicableEu
MoventigTablet, film coated12.5 mgOralKyowa Kirin Limited2014-12-08Not applicableEu
Categories
UNII
44T7335BKE
CAS number
854601-70-0
Weight
Average: 651.794
Monoisotopic: 651.361861531
Chemical Formula
C34H53NO11
InChI Key
XNKCCCKFOQNXKV-ZRSCBOBOSA-N
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
IUPAC Name
(1S,5R,13R,14S,17S)-14-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-4-(prop-2-en-1-yl)-12-oxa-4-azapentacyclo[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]octadeca-7,9,11(18)-triene-10,17-diol
SMILES
COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@@]2(O)[C@H]3CC4=CC=C(O)C5=C4[C@@]2(CCN3CC=C)[C@H]1O5

Pharmacology

Indication

Indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

Associated Conditions
Pharmacodynamics

Use of opioids induces slowing of gastrointestinal motility and transit. Patients do not develop tolerance to these effects, unlike many other opioid side effects. Naloxegol antagonizes mu, delta, and kappa opioid receptors, having the highest affinity for mu. Antagonism of gastrointestinal mu-opioid receptors by naloxegol inhibits opioid-induced delay of gastrointestinal transit time.

Mechanism of action

Naloxegol is an antagonist of opioid binding at the mu-opioid receptor. When administered at the recommended dose levels, naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids. Naloxegol has shown more than 6000 fold selectivity for the peripheral mu receptors, and its PEGylated form restricts its action only to the periphery, not affecting the pain-relieving mechanism of opioids in the central nervous system.

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Human
Absorption

Following oral administration, naloxegol is absorbed with peak concentrations (Cmax) achieved in less than 2 hours.

Volume of distribution

968 to 2140 L.

Protein binding

~4.2%

Metabolism

Naloxegol is metabolized primarily by the CYP P450 3A4 enzyme system and undergoes enterohepatic recycling. In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and feces. These metabolites were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. Human metabolism data suggests absence of major metabolites. The activity of the metabolites at the opioid receptor has not been determined.

Route of elimination

Feces: 68% after oral administration. Urine: 16% after oral administration.

Half life

6-11 hours.

Clearance

Feces (68%), urine (16%).

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Naloxegol can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Naloxegol can be decreased when combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of Naloxegol can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of Naloxegol can be decreased when combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Naloxegol.
5-androstenedioneThe metabolism of Naloxegol can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Naloxegol can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Naloxegol can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe serum concentration of Naloxegol can be increased when it is combined with Abemaciclib.
AbirateroneThe metabolism of Naloxegol can be decreased when combined with Abiraterone.
Food Interactions
  • A high-fat meal increased the extent and rate of naloxegol absorption. The Cmax and AUC were increased by approximately 30% and 45%, respectively. In clinical trials, naloxegol was dosed on an empty stomach approximately 1 hour prior to the first meal in the morning.

References

General References
  1. Leonard J, Baker DE: Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5. doi: 10.1177/1060028014560191. Epub 2014 Dec 3. [PubMed:25471070]
  2. Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK: Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother. 2015 Jul-Sep;6(3):188-92. doi: 10.4103/0976-500X.162015. [PubMed:26312011]
  3. Jones R, Prommer E, Backstedt D: Naloxegol: A Novel Therapy in the Management of Opioid-Induced Constipation. Am J Hosp Palliat Care. 2015 Jul 6. pii: 1049909115593937. [PubMed:26150678]
External Links
KEGG Drug
D10479
PubChem Compound
56959087
PubChem Substance
310264993
ChemSpider
28651656
ChEBI
82975
ChEMBL
CHEMBL2219418
Drugs.com
Drugs.com Drug Page
Wikipedia
Naloxegol
ATC Codes
A06AH03 — Naloxegol
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (530 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAmount of NKTR-118 in Blood / Variation in the Heart's Electrical Cycle1
1CompletedBasic ScienceBioavailability / Drug- Drug Interactions / Healthy Volunteers1
1CompletedBasic ScienceBioavailability / Healthy Volunteers1
1CompletedBasic ScienceDrug Induced Constipation2
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic ScienceHepatic; Functional Disturbance1
1CompletedBasic ScienceOpioid Induced Constipation (OIC)1
1CompletedTreatmentConstipation Drug Induced / Healthy Volunteers1
1RecruitingTreatmentConstipation, Signs and Symptoms, Digestive1
2CompletedTreatmentOpioid Induced Constipation (OIC)1
2Not Yet RecruitingTreatmentGastroparesis / Opioids Use1
2RecruitingSupportive CareAdenocarcinoma of Lung Stage IV / Stage IIIB Lung Adenocarcinoma / Stage IIIb Non-small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer1
2RecruitingTreatmentEsophagus Disorder / Opioid-Induced Disorders1
2RecruitingTreatmentOccasional Constipation1
2, 3RecruitingTreatmentConstipation Drug Induced / Occasional Constipation1
3CompletedTreatmentOpioid Induced Constipation (OIC)4
3Not Yet RecruitingTreatmentCritical Illness / Occasional Constipation1
3TerminatedTreatmentOpioid Induced Constipation (OIC)1
4CompletedTreatmentMalignancies / Occasional Constipation / Pain NOS1
4CompletedTreatmentOpioid Induced Constipation (OIC)1
4Not Yet RecruitingTreatmentConstipation Drug Induced1
4RecruitingPreventionOccasional Constipation1
4RecruitingTreatmentPostoperative pain1
4TerminatedPreventionOccasional Constipation1
Not AvailableNot Yet RecruitingNot AvailableOpioid Induced Constipation (OIC)2
Not AvailableRecruitingNot AvailableOpioid Induced Constipation (OIC)3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral12.5 mg
TabletOral25 mg
Tablet, film coatedOral12.5 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral12.5 mg
Tablet, film coatedOral25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8067431No2011-11-292024-12-16Us
US8617530No2013-12-312022-10-18Us
US7056500No2006-06-062024-06-29Us
US7662365No2010-02-162022-10-18Us
US9012469No2015-04-212032-04-02Us
US7786133No2010-08-312027-12-19Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0566 mg/mLALOGPS
logP1.73ALOGPS
logP1.36ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)10.14ChemAxon
pKa (Strongest Basic)8.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area126.77 Å2ChemAxon
Rotatable Bond Count24ChemAxon
Refractivity171.68 m3·mol-1ChemAxon
Polarizability72.87 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenanthrenes and derivatives
Sub Class
Not Available
Direct Parent
Phenanthrenes and derivatives
Alternative Parents
Tetralins / Coumarans / Aralkylamines / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Piperidines / Tertiary alcohols / Trialkylamines / Cyclic alcohols and derivatives / 1,2-aminoalcohols
show 5 more
Substituents
Phenanthrene / Tetralin / Coumaran / 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Aralkylamine / Piperidine / Cyclic alcohol / Tertiary alcohol / 1,2-aminoalcohol
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary alcohol, aromatic ether, phenols, organic heteropentacyclic compound, polyether (CHEBI:82975)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Leonard J, Baker DE: Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5. doi: 10.1177/1060028014560191. Epub 2014 Dec 3. [PubMed:25471070]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Leonard J, Baker DE: Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5. doi: 10.1177/1060028014560191. Epub 2014 Dec 3. [PubMed:25471070]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Leonard J, Baker DE: Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5. doi: 10.1177/1060028014560191. Epub 2014 Dec 3. [PubMed:25471070]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Leonard J, Baker DE: Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5. doi: 10.1177/1060028014560191. Epub 2014 Dec 3. [PubMed:25471070]
  2. Australian Public Assessment Report: Naloxegol [File]

Drug created on May 04, 2015 17:26 / Updated on November 17, 2018 07:23