Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C32H34N4O6 |
Molecular Weight | 570.6356 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)(NC(=O)C1=C(O)[C@@H]2OC3=C(O)C=CC4=C3[C@@]25CCN(CC6CC6)[C@H](C4)[C@]5(O)C1)C7=NC(=NO7)C8=CC=CC=C8
InChI
InChIKey=AXQACEQYCPKDMV-RZAWKFBISA-N
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
Molecular Formula | C32H34N4O6 |
Molecular Weight | 570.6356 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Naldemedine (Symproic) is an opioid antagonist indicated for the treatment of opioid-induced
constipation (OIC) in adult patients with chronic non-cancer
pain. Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors.
Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the
gastrointestinal tract, thereby decreasing the constipating effects of opioids. Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular
weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB).
Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the
CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the
potential for interference with centrally-mediated opioid analgesia. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.
CNS Activity
Curator's Comment: Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular
weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB).
Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the
CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the
potential for interference with centrally-mediated opioid analgesia.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL270 |
161.08 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Secondary | Symproic Approved UseSYMPROIC is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. Launch Date2017 |
|||
Secondary | SYMPROIC Approved UseSYMPROIC is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain Launch Date2017 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1.98 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28960888 |
0.1 mg single, oral dose: 0.1 mg route of administration: Oral experiment type: SINGLE co-administered: |
NALDEMEDINE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11.6 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28960888 |
0.1 mg single, oral dose: 0.1 mg route of administration: Oral experiment type: SINGLE co-administered: |
NALDEMEDINE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
8.3 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28960888 |
0.1 mg single, oral dose: 0.1 mg route of administration: Oral experiment type: SINGLE co-administered: |
NALDEMEDINE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Doses
Dose | Population | Adverse events |
---|---|---|
100 mg single, oral Highest studied dose |
healthy, 21.8 years n = 6 Health Status: healthy Age Group: 21.8 years Sex: M Population Size: 6 Sources: |
Other AEs: Abdominal pain, Diarrhea... |
30 mg 1 times / day multiple, oral Highest studied dose Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: |
healthy, 28.3 years n = 9 Health Status: healthy Age Group: 28.3 years Sex: M Population Size: 9 Sources: |
Other AEs: Abdominal discomfort, Diarrhea... Other AEs: Abdominal discomfort (11.1%) Sources: Diarrhea (11.1%) |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Disc. AE: Abdominal pain, Diarrhea... AEs leading to discontinuation/dose reduction: Abdominal pain (3.2%) Sources: Page: p. 189Diarrhea (3.2%) Vomiting (3.2%) Nausea (3.2%) Colitis (0.1%) Diverticulitis (0.1%) Hematochezia (0.1%) Transaminases abnormal (0.5%) Edema peripheral (0.1%) Hyperglycemia (0.1%) Insomnia (0.1%) Generalized spasm (0.1%) Paralysis (0.1%) Photosensitivity (0.1%) Rash (0.1%) Thrombosis (0.1%) Supraventricular tachycardia (0.1%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Abdominal pain | 16.7% | 100 mg single, oral Highest studied dose |
healthy, 21.8 years n = 6 Health Status: healthy Age Group: 21.8 years Sex: M Population Size: 6 Sources: |
Diarrhea | 16.7% | 100 mg single, oral Highest studied dose |
healthy, 21.8 years n = 6 Health Status: healthy Age Group: 21.8 years Sex: M Population Size: 6 Sources: |
Abdominal discomfort | 11.1% | 30 mg 1 times / day multiple, oral Highest studied dose Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: |
healthy, 28.3 years n = 9 Health Status: healthy Age Group: 28.3 years Sex: M Population Size: 9 Sources: |
Diarrhea | 11.1% | 30 mg 1 times / day multiple, oral Highest studied dose Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: |
healthy, 28.3 years n = 9 Health Status: healthy Age Group: 28.3 years Sex: M Population Size: 9 Sources: |
Colitis | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Diverticulitis | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Edema peripheral | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Generalized spasm | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Hematochezia | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Hyperglycemia | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Insomnia | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Paralysis | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Photosensitivity | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Rash | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Supraventricular tachycardia | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Thrombosis | 0.1% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Transaminases abnormal | 0.5% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Abdominal pain | 3.2% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Diarrhea | 3.2% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Nausea | 3.2% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Vomiting | 3.2% Disc. AE |
0.2 mg 1 times / day steady, oral Recommended Dose: 0.2 mg, 1 times / day Route: oral Route: steady Dose: 0.2 mg, 1 times / day Sources: Page: p. 189 |
unhealthy, adult n = 1163 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 1163 Sources: Page: p. 189 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Drug as victim
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208854Orig1s000PharmR.pdf#page=238 Page: 238.0 |
PubMed
Title | Date | PubMed |
---|---|---|
Naldemedine (Symproic) for opioid-induced constipation. | 2017 Dec 4 |
|
Formulary Drug Review: Naldemedine. | 2017 Jul |
|
Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy. | 2018 |
|
Evidence Based Review of Pharmacotherapy for Opioid-Induced Constipation in Noncancer Pain. | 2018 Apr |
|
Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers. | 2018 Jun |
|
Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis. | 2018 Oct |
Patents
Sample Use Guides
Administration (2.1):
• Alteration of analgesic dosing regimen prior to initiating SYMPROIC is not required
• Patients receiving opioids for less than 4 weeks may be less responsive to SYMPROIC
• Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued
Dosage (2.2):
• The recommended dosage of SYMPROIC is 0.2 mg orally once daily with or without food.
Route of Administration:
Oral
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 01:29:29 GMT 2023
by
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on
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Record UNII |
03KSI6WLXH
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Validated (UNII)
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Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT | |||
|
TARGET -> INHIBITOR |
Used recombinant human kappa-opioid receptor (expressed in HEK-293 cells), U-50488H as an agonist, and guanosine-5’-O-(3-(35S)thio) triphosphate ((35S)-GTP.GAMMA.S) as a ligand
ANTAGONIST
Kb
|
||
|
TARGET -> INHIBITOR |
Used recombinant human mu-opioid receptor (expressed in CHO-K1 cells), DAMGO as an agonist, and guanosine-5’-O-(3-(35S)thio) triphosphate ((35S)-GTP.GAMMA.S) as a ligand
ANTAGONIST
Kb
|
||
|
TARGET -> INHIBITOR |
RECOMBINANT HUMAN KAPPA-OPIOID RECEPTOR (EXPRESSED IN HEK-293 CELLS), (3H)-U69593 AS A LIGAND
BINDING
Ki
|
||
|
TARGET -> INHIBITOR |
Kobs of (3H)-Naloxone was 0.233 (1/min).
BINDING
Association rate constant (Kobs)
|
||
|
TRANSPORTER -> SUBSTRATE |
|
||
|
TARGET -> INHIBITOR |
RECOMBINANT HUMAN DELTA-OPIOID RECEPTOR (EXPRESSED IN HEK-293 CELLS), (3H)-(D-ALA2, D-LEU5)-ENKEPHALIN (DADLE) AS A LIGAND
BINDING
Ki
|
||
|
TARGET -> INHIBITOR |
T1/2 of (3H)-Naloxone was 0.266 min.
BINDING
T1/2 (the time until binding of the radiolabelled ligand to the receptor decreases to 50% after addition of an excess amount of unlabeled ligand)
|
||
|
BINDER->LIGAND |
BINDING
|
||
|
TARGET -> INHIBITOR |
Based on slope of Schild regression, naldemedine monotosylate exhibited non-competitive antagonism to morphine, oxycodone, hydrocodone, and fentanyl-induced (35S)-GTP.gamma.S binding.
NON-COMPETITIVE INHIBITOR
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
|
||
|
TARGET -> INHIBITOR |
RECOMBINANT HUMAN MU-OPIOID RECEPTER (EXPRESSED IN CHO-K1 CELLS), (3H)-(D-ALA2, N-ME-PHE4, GLY5-OL)-ENKEPHALIN ACETATE SALT (DAMGO) AS A LIGAND
BINDING
Ki
|
||
|
TARGET -> INHIBITOR |
Used recombinant human delta-opioid receptor (expressed in HEK-293 cells), (Met5)-enkephalin as an agonist, and guanosine-5’-O-(3-(35S)thio) triphosphate ((35S)-GTP.GAMMA.S) as a ligand
ANTAGONIST
Kb
|
||
|
TARGET -> INHIBITOR |
Koff of (3H)-Naloxone was 0.266 (1/min).
BINDING
Dissociation rate constant (Koff)
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Related Record | Type | Details | ||
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METABOLITE LESS ACTIVE -> PARENT | |||
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METABOLITE LESS ACTIVE -> PARENT | |||
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METABOLITE INACTIVE -> PARENT | |||
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METABOLITE LESS ACTIVE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE INACTIVE -> PARENT |
Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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Volume of Distribution | PHARMACOKINETIC |
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