VARENICLINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C13H13N3
Molecular Weight	211.2624
Optical Activity	NONE
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C1[C@H]2CNC[C@@H]1C3=CC4=C(C=C23)N=CC=N4

InChI

InChIKey=JQSHBVHOMNKWFT-DTORHVGOSA-N

InChI=1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9+

HIDE SMILES / InChI

Description
Sources: https://www.drugbank.ca/drugs/DB01273
Curator's Comment: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021928s039s041lbl.pdf

Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain. Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectiviyty for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms. Varenicline is sold under the trade name Chantix and Champix, it is indicated for use as an aid to smoking cessation treatment.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Neuronal acetylcholine receptor; alpha4/beta2 76 Target ID: CHEMBL1907589 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021928s039s041lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/22591063 \| https://www.ncbi.nlm.nih.gov/pubmed/16766716	Partial Agonist 290		0.4 nM [Ki]
Neuronal acetylcholine receptor protein alpha-7 subunit 77 Target ID: CHEMBL2492 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24406270	Agonist 2678		130.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Nicotine dependence 32 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021928s039s041lbl.pdf	Curative		Approved 8429	CHANTIX Approved Use CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to smoking cessation treatment. Launch Date 2006

C_max

Value	Dose	Analyte	Population
6.38 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: UNKNOWN
5.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920893/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
9.22 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg 2 times / day multiple, oral dose: 1 mg route of administration: Oral experiment type: MULTIPLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
106 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: UNKNOWN
97.7 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920893/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
186 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19916991/	1 mg 2 times / day steady-state, oral dose: 1 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	VARENICLINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
194 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg 2 times / day multiple, oral dose: 1 mg route of administration: Oral experiment type: MULTIPLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
10.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: UNKNOWN
11.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920893/	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
24 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19916991/	1 mg 2 times / day steady-state, oral dose: 1 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	VARENICLINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
33 h REVIEW https://pubmed.ncbi.nlm.nih.gov/21053991/	1 mg 2 times / day multiple, oral dose: 1 mg route of administration: Oral experiment type: MULTIPLE co-administered:	VARENICLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
1 mg 2 times / day multiple, oral Recommended Dose: 1 mg, 2 times / day Route: oral Route: multiple Dose: 1 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22007690 Page: p.15	unhealthy, 46 n = 36 Health Status: unhealthy Condition: Smoking addiction Age Group: 46 Sex: M+F Population Size: 36 Sources: https://pubmed.ncbi.nlm.nih.gov/22007690 Page: p.15	Disc. AE: Nausea, Anger... AEs leading to discontinuation/dose reduction: Nausea (4%) Anger (1%) Insomnia (1%) Sources: https://pubmed.ncbi.nlm.nih.gov/22007690 Page: p.15
15 mg single, oral Overdose Dose: 15 mg Route: oral Route: single Dose: 15 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19274508	healthy Health Status: healthy Sources: https://pubmed.ncbi.nlm.nih.gov/19274508	Disc. AE: Vomiting, Tachycardia... AEs leading to discontinuation/dose reduction: Vomiting Tachycardia Sources: https://pubmed.ncbi.nlm.nih.gov/19274508
1 mg 2 times / day multiple, oral Recommended Dose: 1 mg, 2 times / day Route: oral Route: multiple Dose: 1 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Smoking addiction Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1	Disc. AE: Psychiatric disorder NOS, Suicidal ideation... AEs leading to discontinuation/dose reduction: Psychiatric disorder NOS (serious) Suicidal ideation (serious) Suicidal behavior (serious) Agitation Hostility Depressed mood Angioedema Hypersensitivity reaction Reaction skin (grade 3-4, rare) Accidental injury Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1
1 mg 2 times / day multiple, oral Recommended Dose: 1 mg, 2 times / day Route: oral Route: multiple Dose: 1 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1,3	unhealthy Health Status: unhealthy Condition: Smoking addiction Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1,3	Disc. AE: Nausea... AEs leading to discontinuation/dose reduction: Nausea (3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf Page: p.1,3

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP3A4/5 278 P-gp 1461 OCT2 647	OCT2 355 P-gp 1537 CYP 270 UGT enzymes 27	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no [IC50 >30 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0	no	no (co-administration study) Comment: digoxin remained unchanged in the presence of varenicline Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_PharmR.pdf Page: 72.0	weak

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 35.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0	no	no (co-administration study) Comment: digoxin remained unchanged in the presence of varenicline Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 36.0
UGT enzymes 27	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_BioPharmR.pdf Page: 37, 272, 276	yes
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_PharmR.pdf Page: 46, 72	yes	yes (co-administration study) Comment: cimetidine increased the systemic exposure of varenicline by 29% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_PharmR.pdf Page: 46, 72

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chantix_PharmR.pdf Page: 39.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:84500	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:84500
MolPort	MolPort-006-167-759	https://www.molport.com/shop/molecule-link/MolPort-006-167-759
ZINC	ZINC000001481833	http://zinc15.docking.org/substances/ZINC000001481833
eMolecules	36500513	https://www.emolecules.com/cgi-bin/more?vid=36500513

PubMed

Title	Date	PubMed
Gateways to clinical trials.	2005 Jun	16082422
[Medication for ending tobacco dependency. Current state].	2005 Jun 30	15989825
3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.	2005 Nov 15	16171993
Pharmacotherapy for nicotine dependence.	2005 Sep-Oct	16166074
Treating smoking dependence in depressed alcoholics.	2006	17373412
[New tobacco dependence drug: Varenicline, partial agonist of alpha4beta2 acetylcholine-nicotine receptors].	2006	17168413
Molecule of the Month. Varenicline tartrate.	2006 Apr	16804568
A rationale and model for addressing tobacco dependence in substance abuse treatment.	2006 Aug 14	16907984
Varenicline (Chantix) for tobacco dependence.	2006 Aug 14-28	16977281
Varenicline: new drug. Smoking cessation: no better than nicotine.	2006 Dec	17165237
Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers.	2006 Dec	17101743
Effectiveness of smoking cessation therapies: a systematic review and meta-analysis.	2006 Dec 11	17156479
Efficacy of varenicline for smoking cessation.	2006 Dec 6	17148718
FDA speeds smoking cessation drug review.	2006 Feb 8	16467225
Developments in pharmacotherapy for tobacco dependence: past, present and future.	2006 Jan	16492578
Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro.	2006 Jan	16221753
Varenicline.	2006 Jul	16883648
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.	2006 Jul 5	16820546
The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline.	2006 May	16700857
Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers.	2006 Nov	17050788
Trials that matter: varenicline: a designer drug to help smokers quit.	2006 Nov 21	17116925
Smoking: tackling the silent epidemic.	2007	17824207
[Varenicline (Champix)].	2007	17508668
[Tobacco use prevention and cessation in the dental practice].	2007	17425242
Non-nicotinic therapies for smoking cessation.	2007	17209799
Mechanism of varenicline (clinical ramifications): electron transfer and oxidative stress.	2007	17127014
An employer-based cost-benefit analysis of a novel pharmacotherapy agent for smoking cessation.	2007 Apr	17426529
A double-blind study evaluating the long-term safety of varenicline for smoking cessation.	2007 Apr	17407636
Optimizing on smoke free legislation making the most of the opportunity.	2007 Aug	17851296
Smoking cessation in patients with respiratory diseases: a high priority, integral component of therapy.	2007 Feb	17264326
Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.	2007 Feb	17259946
[Giving up smoking is crucial for COPD patients].	2007 Feb 22	17615702
Oral varenicline for smoking cessation.	2007 Jan	17190845
Advances in the management of chronic obstructive pulmonary disease.	2007 Jan	17163804
Dopamine D3 receptor ligands for the treatment of tobacco dependence.	2007 Jan	17155853
Antidepressants for smoking cessation.	2007 Jan 24	17253443
How well does the new drug varenicline work for people who want to stop smoking?	2007 Jun	17657893
The most addictive drug, the most deadly substance: smoking cessation tactics for the busy clinician.	2007 Mar	17481990
[Varenicline--a new drug for smoking cessation].	2007 Mar	17405480
Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.	2007 Mar	17157884
Alcohol history and smoking cessation in nicotine replacement therapy, bupropion sustained release and varenicline trials: a review.	2007 May-Jun	17526629
Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for smoking cessation.	2007 May-Jun	17438382
Cytisine for smoking cessation: a research agenda.	2008 Jan 1	17825502

Patents

Sample Use Guides

In Vivo Use Guide

Begin CHANTIX (Varenicline) dosing one week before the date set by the patient to stop smoking. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment. (2.1) • Starting week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on days 4-7. (2.1) • Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1) • An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence. (2.1) • Consider a gradual approach to quitting smoking with CHANTIX for patients who are sure that they are not able or willing to quit abruptly. Patients should begin CHANTIX dosing and reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the goal of reaching complete abstinence by 12 weeks. Continue treatment for an additional 12 weeks, for a total of 24 weeks. (2.1) CHANTIX should be taken orally after eating and with a full glass of water.

Route of Administration: Oral

In Vitro Use Guide

Varenicline potently desensitized the α4β2 nAChR with IC50 value of 420 nM

Name

Type

Language

VARENICLINE

Official Name

English

VARENICLINE [MI]

Common Name

English

CP-526,555

Code

English

VARENICLINE [EMA EPAR]

Common Name

English

VARENICLINE [HSDB]

Common Name

English

VARENICLINE [VANDF]

Common Name

English

VARENICLINE [MART.]

Common Name

English

CP-526555

Code

English

7,8,9,10-TETRAHYDRO-6H-6,10-METHANOAZEPINO(4,5-G)QUINOXALINE

Systematic Name

English

varenicline [INN]

Common Name

English

Varenicline [WHO-DD]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175702