Naldemedine

Identification

Summary

Naldemedine is an opioid antagonist used to to treat opioid-induced constipation.

Brand Names
Symproic
Generic Name
Naldemedine
DrugBank Accession Number
DB11691
Background

Naldemedine is an opioid receptor antagonist Label. It is a modified form of Naltrexone to which a side chain has been added to increase molecular weight and polar surface area resulting in restricted transport across the blood brain barrier. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 570.646
Monoisotopic: 570.247834831
Chemical Formula
C32H34N4O6
Synonyms
  • Naldemedine
External IDs
  • S-297995

Pharmacology

Indication

For the treatment of opioid-induced constipation Label.

Pharmacology
Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

Naldemedine is an opioid receptor antagonist with restricted movement across the blood brain barrier Label. This allows it to antagonize the periperal effects of opioid drugs such as constipation without interfering with the effects on the central nervous system.

Mechanism of action

Naldemedine binds to and antagonizes mu-, delta-, and kappa-opioid receptors Label. The binding of opioid agonists to peripheral mu-opioid receptors slows the transit of feces through the intestine resulting in constipation. By antagonizing mu-opioid receptors, naldemedine inhibits this effect.

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Humans
ADelta-type opioid receptor
antagonist
Humans
AKappa-type opioid receptor
antagonist
Humans
Absorption

Tmax is 0.75 h Label. Administration with a high-fat meal reduces Cmax by 35% and increases Tmax to 2.5 h.

Volume of distribution

The apparent volume of disribution during the terminal phase is 155 L Label

Protein binding

Naldemedine is 93-94% bound to human plasma proteins Label.

Metabolism

Naldemedine is mainly metabolized to nor-naldemedine by CYP3A Label. Some metabolism to naldemedine-3-glucuronide occurs via UGT1A3. Both metabolites are acitive but less potent than naldemedine. The relative exposures of these metabolites are 9-13% and <3% for nor-naldemedine and naldemedine-3-glucuronide respectively. Naldemedine is also cleaved in the intestine to form benzamidine and naldemedine carboxylic acid.

Route of elimination

57% of naldemedine is excreted in the urine with 16-18% as the parent compound and 35% is excreted in the feces Label.

Half-life

The terminal elimination half life is 11 h Label.

Clearance

Not Available

Adverse Effects
Adverseeffects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

The most common adverse effects of naldemedine are abdominal pain (11%), diarrhea (7%), nausea (6%), vomiting (3%), and gastroenteritis (3%) Label.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Naldemedine which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Naldemedine which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Naldemedine which could result in a higher serum level.
Interactions
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
Food Interactions
  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of naldemedine.
  • Take with or without food.

Products

Products2
Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Naldemedine tosylateV1N8F1RVVO1345728-04-2WCYDLROFMZJJLE-RTMHEQJQSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-16Not applicableEU flag
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-16Not applicableEU flag
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-16Not applicableEU flag
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-16Not applicableEU flag
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-21Not applicableEU flag
RizmoicTablet, film coated200 mcgOralShionogi B.V.2020-12-16Not applicableEU flag
SymproicTablet.2 mg/1OralPurdue Pharma LP2017-03-232020-12-31US flag
SymproicTablet0.2 mg/1OralSHIONOGI INC.2018-07-052020-12-31US flag
SymproicTablet0.2 mg/1OralBioDelivery Sciences International Inc2019-06-14Not applicableUS flag

Categories

ATC Codes
A06AH05 — Naldemedine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Morphinans
Sub Class
Not Available
Direct Parent
Morphinans
Alternative Parents
Phenanthrenes and derivatives / Phenyloxadiazoles / Tetralins / Coumarans / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Piperidines / Benzene and substituted derivatives / Vinylogous acids
show 13 more
Substituents
1,2,4-oxadiazole / 1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle
show 31 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
03KSI6WLXH
CAS number
916072-89-4
InChI Key
AXQACEQYCPKDMV-RZAWKFBISA-N
InChI
InChI=1S/C32H34N4O6/c1-30(2,29-33-27(35-42-29)18-6-4-3-5-7-18)34-28(39)20-15-32(40)22-14-19-10-11-21(37)25-23(19)31(32,26(41-25)24(20)38)12-13-36(22)16-17-8-9-17/h3-7,10-11,17,22,26,37-38,40H,8-9,12-16H2,1-2H3,(H,34,39)/t22-,26+,31+,32-/m1/s1
IUPAC Name
(1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,14,17-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7,9,11(18),14-tetraene-15-carboxamide
SMILES
[H][C@@]12OC3=C4C(C[C@@]5([H])N(CC6CC6)CC[C@@]14[C@@]5(O)CC(C(=O)NC(C)(C)C1=NC(=NO1)C1=CC=CC=C1)=C2O)=CC=C3O

References

General References
  1. FDA Approved Drug Products: Symproic (naldemidine tosylate) tablets for oral use [Link]
PubChem Compound
54732242
PubChem Substance
347828056
ChemSpider
28530803
BindingDB
50503604
RxNav
1876597
ChEMBL
CHEMBL2105755
Wikipedia
Naldemedine
FDA label
Download (209 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentOpioid Induced Constipation (OIC)3
2CompletedTreatmentOpioid Induced Bowel Dysfunction1
2CompletedTreatmentOpioid Induced Constipation (OIC)1
2TerminatedTreatmentPostoperative Gastrointestinal Dysfunction1
2, 3Not Yet RecruitingPreventionAcute Pancreatitis1
Not AvailableRecruitingNot AvailableOpioid Induced Constipation (OIC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral200 MCG
TabletOral.2 mg/1
TabletOral0.2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9108975No2015-08-182031-11-11US flag
USRE46365No2017-04-112028-01-11US flag
USRE46375No2017-04-252026-10-05US flag
US10952968No2013-05-132033-05-13US flag

Properties

State
Not Available
Experimental Properties
PropertyValueSource
water solubilitySlightly solubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.227 mg/mLALOGPS
logP3.14ALOGPS
logP2.43ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)9.86ChemAxon
pKa (Strongest Basic)9.05ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area141.18 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity165.78 m3·mol-1ChemAxon
Polarizability61.34 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability1ChemAxon
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

Targets

Drugtargets2
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Humans
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
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
No
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...

Components:
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da

Drug created on October 20, 2016 20:40 / Updated on August 13, 2021 04:44