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
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.	2007 Oct	17656655
Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study.	2008 Dec	19020157
The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunionectomy) surgery .	2008 Nov	18851776
Tapentadol a 'realistic alternative' to strong opioids for severe pain.	2008 Sep	18819294
Tapentadol hydrochloride: a centrally acting oral analgesic.	2009 Dec	20110020
Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study.	2009 Feb	19302899
Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.	2009 Jul	19834626
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
A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain.	2009 Mar	19203298
Schedules of controlled substances: placement of tapentadol into schedule II. Final rule.	2009 May 21	19507329
Is tapentadol an advance on tramadol?	2009 Nov	20092221
Tapentadol immediate release for the relief of moderate-to-severe acute pain.	2009 Nov	19795998
The importance of the descending monoamine system for the pain experience and its treatment.	2009 Oct 29	20948695
Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study.	2010 Aug	20578811
[Tapentadol. Opioid analgesic and norepinephrine reuptake inhibitors].	2010 Dec	21189520
Advances in perioperative pain management: use of medications with dual analgesic mechanisms, tramadol & tapentadol.	2010 Dec	21074743
Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain.	2010 Feb 12	20026182
In vitro and in vivo characterization of tapentadol metabolites.	2010 Jan-Feb	20383344
Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution?	2010 Jul	20465361
Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain.	2010 Jun	20556560
Tapentadol immediate-release for acute pain.	2010 Jun	20518601
Neuropathy, retinopathy, and glucose-lowering treatments.	2010 Jun	20508223
Recent advances in postoperative pain management.	2010 Mar	20351978
Determination of tapentadol and its metabolite N-desmethyltapentadol in urine and oral fluid using liquid chromatography with tandem mass spectral detection.	2010 Oct	21819790
Analgesic update: tapentadol hydrochloride.	2010 Oct	20960989
A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects.	2010 Oct	20875374
Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.	2010 Oct	20818833
Cost-effectiveness analysis of tapentadol immediate release for the treatment of acute pain.	2010 Sep	21194601
Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon?	2010 Sep	20659810
Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.	2010 Sep	20541444
Tapentadol immediate release: a review of its use in the treatment of moderate to severe acute pain.	2010 Sep 10	20731478

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