TAPENTADOL MALEATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H23NO.C4H4O4
Molecular Weight	337.4107
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C/C(O)=O.CC[C@H]([C@@H](C)CN(C)C)C1=CC=CC(O)=C1

InChI

InChIKey=JVHIGTLVLBJREO-HQOQZQJTSA-N

InChI=1S/C14H23NO.C4H4O4/c1-5-14(11(2)10-15(3)4)12-7-6-8-13(16)9-12;5-3(6)1-2-4(7)8/h6-9,11,14,16H,5,10H2,1-4H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t11-,14+;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17656655
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/21476608 | https://www.nucynta.com/hcp/er/mechanism-of-action#isi-0

Tapentadol is the first US FDA-approved centrally acting analgesic having both μ-opioid receptor agonist and noradrenaline (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. Tapentadol is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Mu opioid receptor 221 Target ID: CHEMBL233 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17656655	Agonist 2678	0.16 µM [Ki]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17656655	Inhibitor 8297	8.8 µM [Ki]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17656655	Inhibitor 8297	5.28 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf	Primary		Approved 8429	NUCYNTA Approved Use NUCYNTA ER (tapentadol) is indicated for the management of: pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Launch Date 2008

C_max

Value	Dose	Co-administered	Analyte	Population
221.34 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/23357834/	86 mg single, oral dose: 86 mg route of administration: Oral experiment type: SINGLE co-administered:		TAPENTADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
221.34 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/23357834/	86 mg single, oral dose: 86 mg route of administration: Oral experiment type: SINGLE co-administered:		TAPENTADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.16 h REVIEW https://pubmed.ncbi.nlm.nih.gov/23357834/	86 mg single, oral dose: 86 mg route of administration: Oral experiment type: SINGLE co-administered:		TAPENTADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022304s022lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		TAPENTADOL plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
80% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022304s022lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		TAPENTADOL plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
250 mg 2 times / day multiple, oral (max) Recommended Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20602712 Page: p.424	unhealthy, 56.8 n = 894 Health Status: unhealthy Condition: Chronic low back pain\|Osteoarthritis pain Age Group: 56.8 Sex: M+F Population Size: 894 Sources: https://pubmed.ncbi.nlm.nih.gov/20602712 Page: p.424	Disc. AE: Nausea, Constipation... AEs leading to discontinuation/dose reduction: Nausea (3.4%) Constipation (1.6%) Dizziness (3%) Vomiting (2.6%) Fatigue (1.8%) Somnolence (3.4%) Pruritus (0.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/20602712 Page: p.424
100 mg 6 times / day multiple, oral Recommended Dose: 100 mg, 6 times / day Route: oral Route: multiple Dose: 100 mg, 6 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.7	unhealthy Health Status: unhealthy Condition: Acute pain Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.7	Disc. AE: Dizziness, Nausea... AEs leading to discontinuation/dose reduction: Dizziness Nausea Vomiting Somnolence Headache Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.7
700 mg 6 times / day multiple, oral (total) Recommended Dose: 700 mg, 6 times / day Route: oral Route: multiple Dose: 700 mg, 6 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Acute pain Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.1	Disc. AE: Respiratory depression, CNS disorder (NOS)... AEs leading to discontinuation/dose reduction: Respiratory depression CNS disorder (NOS) Intracranial pressure increased Abuse NOS Mental function decreased Physical impairment Seizures Serotonin syndrome (grade 4) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf Page: p.1

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767 inducer 389	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2C19 1478 CYP2E1 882	CYP2C19 991	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=82 Page: 82.0	no

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=5 Page: 5.0	yes
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=5 Page: 5.0	yes
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000ClinPharmR.pdf#page=5 Page: 5.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200533Orig1s000PharmR.pdf#page=22 Page: 22.0

Sourcing

Vendor/Aggregator	ID	URL
AK Scientific, Inc. (AKSCI)	4084AH	http://www.aksci.com/item_detail.php?cat=4084AH
Acadechem	ACDS-061982	http://www.acadechemical.com/product/136681
Achemtek	0102-020035	http://www.achemtek.com/175591-23-8
Acorn PharmaTech	ACN-050883	http://www.acornpharmatech.com/
Aurora Fine Chemicals LLC	K16.552.242	http://online.aurorafinechemicals.com/info?ID=K16.552.242
Aurum Pharmatech LLC	B-1798	http://www.Aurumpharmatech.com/Product/ProductDetails/B_1798
Chem Scene	CS-M0020	http://www.chemscene.com/175591-23-8.html
ChemMol	44014575	http://www.chemmol.com/chemmol/44014575.html
ChemMol	49400147	http://www.chemmol.com/chemmol/49400147.html
ChemMol	97300664	http://www.chemmol.com/chemmol/97300664.html
ChemMol	97300665	http://www.chemmol.com/chemmol/97300665.html
Clearsynth	CS-O-02454	https://www.clearsynth.com/en/CSO02454.html
Finetech	FT-0699883	http://www.finetechnology-ind.com/online_service.shtml
Renno Tech	RL02248	http://www.rennotech.com/product_show.asp?id=2497
Sinfoo Biotech	S046325	http://www.sinfoobiotech.com/product/1049723
Smolecule	S544552	http://www.smolecule.com/products/s544552
Specs	AR-270/43507984	http://www.specs.net/enter.php?specsid=AR-270/43507984
Synblock Inc	SB17333	http://www.synblock.com/product/175591-23-8.html
THE BioTek	bt-283455	https://www.thebiotek.com/product/inhibitors/bt-283455
iChemical	EBD44459	http://www.ichemical.com/chemicals/cas-175591-23-8

PubMed

Title	Date	PubMed
Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects.	2007 Jul-Sep	18062408
Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes.	2008 Jan	19356073
Tapentadol approved as pain reliever.	2009 Jan 1	19106337
A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain.	2009 Jun	19445652
Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.	2010	20586515
Stereochemical basis for a unified structure activity theory of aromatic and heterocyclic rings in selected opioids and opioid peptides.	2010 Feb 18	20212915
Tapentadol immediate release: a new treatment option for acute pain management.	2010 Feb 8	21197304
In vitro and in vivo characterization of tapentadol metabolites.	2010 Jan-Feb	20383344
Tapentadol immediate-release for acute pain.	2010 Jun	20518601
Determination of tapentadol (Nucynta®) and N-desmethyltapentadol in authentic urine specimens by ultra-performance liquid chromatography-tandem mass spectrometry.	2010 Oct	21819789
Analgesic update: tapentadol hydrochloride.	2010 Oct	20960989
Cost-effectiveness analysis of tapentadol immediate release for the treatment of acute pain.	2010 Sep	21194601
Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.	2010 Sep-Oct	20602712
Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations.	2013 Apr	23357834
Tapentadol hydrochloride: A novel analgesic.	2013 Jul	24015138

Patents

Sample Use Guides

In Vivo Use Guide

As with many centrally-acting analgesic medications, the dosing regimen of NUCYNTA® should be individualized according to the severity of pain being treated, the previous experience with similar drugs and the ability to monitor the patient. Initiate NUCYNTA® with or without food at a dose of 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are, therefore, not recommended.

Route of Administration: Oral

In Vitro Use Guide

Upon exposure to tramadol and tapentadol concentrations up to 600μM, cell toxicity was assessed through evaluation of oxidative stress, mitochondrial and metabolic alterations, as well as cell viability and death mechanisms through necrosis or apoptosis, and related signalling. Tapentadol was observed to trigger much more prominent toxic effects than tramadol, ultimately leading to energy deficit and cell death.

Name

Type

Language

TAPENTADOL MALEATE

Common Name

English

PHENOL, 3-((1R,2R)-3-(DIMETHYLAMINO)-1-ETHYL-2-METHYLPROPYL)-, (2Z)-2-BUTENEDIOATE (1:1)

Systematic Name

English

TAPENTADOL MALEATE (1:1)

Common Name

English

Code System Code Type Description

CAS

1443156-37-3