Venetoclax

Explore a selection of our essential drug information below, or:

Unlock enhanced features & extensive drug insights, including detailed interaction data & regulatory status. Create a free account.

SUBSCRIBERECOMMENDED FOR PHARMA

Explore the full scope of our drug knowledge tailored for pharmaceutical research needs in our data library. Learn more.

Overview

Description: A medication used to treat some types of leukemia and cancer affecting cells of the immune system.
Structure
Description: A medication used to treat some types of leukemia and cancer affecting cells of the immune system.
DrugBank ID: DB11581
Type: Small Molecule
US Approved: YES
Other Approved: YES
Patents: 10
Indicated Conditions: 3
Clinical Trials: Phase 0
4
Phase 1
283
Phase 2
376
Phase 3
52
Phase 4
3
Therapeutic Categories: BCL-2 Inhibitor
Mechanism of Action: Apoptosis regulator Bcl-2
Antagonist
Inhibitor

Identification

Summary

Venetoclax is a BCL-2 inhibitor used to treat chronic lymphocytic leukemia, small lymphocytic lymphoma, or acute myeloid leukemia.

Brand Names

Venclexta

Generic Name

Venetoclax

DrugBank Accession Number

DB11581

Background

Venetoclax is a BCL-2 inhibitor that was initially approved by the FDA in April 2016 ^Label. Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are important regulators of the apoptotic (programmed cell death) process ¹, ². Venetoclax is used to treat chronic lymphocytic leukemia (CLL) and certain types of small lymphocytic lymphoma ^Label. CLL is the most prevalent leukemia diagnosed in Western countries ⁷. Venetoclax was developed through reverse engineering of the BCL-2 protein family inhibitor, navitoclax ⁷. Venetoclax is approximately 10 times more potent than navitoclax with regard to induction of apoptosis in CLL cells ⁷. A new indication was approved in 2018 for the treatment patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy ^Label. Previously, this drug was indicated only for patients with 17p gene deletion ¹¹.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 868.45
Monoisotopic: 867.3180959
Chemical Formula: C₄₅H₅₀ClN₇O₇S

Synonyms

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzene-1-sulfonyl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide

External IDs

ABT 199
ABT-199
ABT199
GDC 0199
GDC-0199
GDC0199
RG 7601
RG-7601
RG7601

Get Early Access To DrugBank+

Be among the first to try our new AI-powered, game-changing platform. DrugBank+ is here to streamline your pharmaceutical research and deliver faster insights and smarter decisions.

Join the Waitlist

Get Early Access To DrugBank+

Join the Waitlist

Pharmacology

Indication

Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is also used in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.⁹

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

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics
Used in combination to treat	Acute myeloid leukemia (aml)	Regimen in combination with: Azacitidine (DB00928)	••••••••••••	•••••	••••• •••••••••• •••••••••••••
Used in combination to treat	Acute myeloid leukemia (aml)	Regimen in combination with: Decitabine (DB01262)	••••••••••••	•••••	••••• •••••••••• •••••••••••••
Used in combination to treat	Acute myeloid leukemia (aml)	Regimen in combination with: Cytarabine (DB00987)	••••••••••••	•••••	•••••••••••••• ••••• •••••••••
Treatment of	Chronic lymphocytic leukemia (cll)		••••••••••••	•••••
Treatment of	Small lymphocytic lymphoma		••••••••••••	•••••

Contraindications & Blackbox Warnings

Prevent Adverse Drug Events Today

Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.

Learn more

Avoid life-threatening adverse drug events with our Clinical API

Learn more

Pharmacodynamics

Venetoclax induces rapid and potent onset apoptosis of CLL cells, powerful enough to act within 24h and to lead to tumor lysis syndrome ⁵, ^Label, ². Selective targeting of BCL2 with venetoclax has demonstrated a manageable safety profile and has been shown to induce significant response in patients with relapsed CLL (chronic lymphocytic leukemia) or SLL (small lymphocytic leukemia), including patients with poor prognostic features ⁶. This drug is not expected to have a significant impact on the cardiac QT interval ^Label. Venetoclax has demonstrated efficacy in various types of lymphoid malignancies, including relapsed/ refractory CLL harboring deletion 17p, with an overall response rate of approximately 80% ⁷.

Mechanism of action

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are necessary regulators of the apoptotic (anti-cell programmed death) process. This family comprises proapoptotic and prosurvival proteins for various cells. Cancer cells evade apoptosis by inhibiting programmed cell death (apoptosis). The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has demonstrated clinical efficacy in some BCL-2-dependent hematological cancers ¹. Selective inhibition of BCL-2 by venetoclax, sparing BCL-xL enables therapeutic induction of apoptosis without the negative effect of thrombocytopenia ⁷, ¹. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins, leading to mitochondrial outer membrane permeabilization and the activation of caspase enzymes. In nonclinical studies, venetoclax has shown cytotoxic activity in tumor cells that overexpress BCL-2 ^Label.

Target	Actions	Organism
AApoptosis regulator Bcl-2	antagonist inhibitor	Humans

Absorption

Following several oral administrations after a meal, the maximum plasma concentration of venetoclax was reached 5-8 hours after the dose ³. Venetoclax steady state AUC (area under the curve) increased proportionally over the dose range of 150-800 mg. After a low-fat meal, venetoclax mean (± standard deviation) steady-state Cmax was 2.1 ± 1.1 μg/mL and AUC0-24 was 32.8 ± 16.9 μg•h/mL at the 400 mg once daily dose ^Label.

When compared with the fasted state, venetoclax exposure increased by 3.4 times when ingested with a low-fat meal and 5.2 times with a high-fat meal. When comparing low versus high fat, the Cmax and AUC were both increased by 50% when ingested with a high-fat meal. The FDA label indicataes that venetoclax should be taken with food ⁷, ^Label.

Volume of distribution

The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L ^Label.

Protein binding

Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 µM (0.87-26 µg/mL). The mean blood-to-plasma ratio was 0.57 ^Label.

Metabolism

In vitro studies demonstrated that venetoclax is predominantly metabolized as a substrate of CYP3A4/5 ^Label, ⁴, ¹⁰.

Hover over products below to view reaction partners

Venetoclax
- M27

Route of elimination

After single oral administration of 200 mg radiolabeled [14C]-venetoclax dose to healthy subjects, >99.9% of the dose was found in feces and <0.1% of the dose was excreted in urine within 9 days, suggesting that hepatic elimination is responsible for the clearance of venetoclax from systemic circulation. Unchanged venetoclax accounted for 20.8% of the radioactive dose excreted in feces ^Label.

Half-life

The half-life of venetoclax is reported to be 19-26 hours, after administration of a single 50-mg dose ⁷, ^Label.

Clearance

Mainly hepatic ^Label.

Adverse Effects

Improve decision support & research outcomes

With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!

See the data

Improve decision support & research outcomes with our structured adverse effects data.

See a data sample

Toxicity

Acute toxicity: oral toxicity (LD50) >2001 mg/kg (mouse) ⁸.

Venetoclax may cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid pregnancy during treatment. A risk to human male fertility exists based on the results of testicular toxicity (germ cell loss) seen in dogs at exposures as low as 0.5 times the human AUC exposure at the recommended dose ^Label.

Carcinogenicity studies have not yet been performed with venetoclax ^Label.

Venetoclax was not shown to be mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce aberrations in an in vitro chromosome aberration assay with human peripheral blood lymphocytes. It was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity during both in vitro Ames and chromosome aberration assays ^Label.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Unlock the secrets to drugging the undruggable

Discover how groundbreaking research is turning "undruggable" targets into therapeutic opportunities.

Download eBook

Unlock the secrets to drugging the undruggable

Download eBook

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.

Drug	Interaction
Integrate drug-drug interactions in your software
1,2-Benzodiazepine	The metabolism of 1,2-Benzodiazepine can be decreased when combined with Venetoclax.
Abametapir	The serum concentration of Venetoclax can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Venetoclax can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Venetoclax.
Abiraterone	The metabolism of Abiraterone can be decreased when combined with Venetoclax.

Food Interactions

Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of venetoclax.
Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of venetoclax.
Take at the same time every day.
Take with a full glass of water.
Take with food.

Products

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

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Venclexta	Tablet	50 mg	Oral	Abbvie	2016-10-31	Not applicable
Venclexta	Tablet, film coated	50 mg/1	Oral	Abbvie	2016-04-11	Not applicable
Venclexta	Tablet	10 mg	Oral	Abbvie	2016-10-31	Not applicable
Venclexta	Tablet, film coated	10 mg/1	Oral	Abbvie	2016-04-11	Not applicable
Venclexta	Tablet	100 mg	Oral	Abbvie	2016-10-31	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Venclexta	Venetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)	Kit; Tablet	Oral	Abbvie	2016-10-31	Not applicable
Venclexta	Venetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)	Kit; Tablet, film coated	Oral	Abbvie	2016-04-11	Not applicable
Venclexta	Venetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)	Kit; Tablet	Oral	Abbvie	2016-10-31	Not applicable
Venclexta	Venetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)	Kit; Tablet, film coated	Oral	Abbvie	2016-04-11	Not applicable
Venclexta	Venetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)	Kit; Tablet	Oral	Abbvie	2016-10-31	Not applicable

Chemical Identifiers

UNII: N54AIC43PW
CAS number: 1257044-40-8
InChI Key: LQBVNQSMGBZMKD-UHFFFAOYSA-N
InChI: InChI=1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)
IUPAC Name: 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzenesulfonyl)-2-{1H-pyrrolo[2,3-b]pyridin-5-yloxy}benzamide
SMILES: CC1(C)CCC(CN2CCN(CC2)C2=CC=C(C(=O)NS(=O)(=O)C3=CC=C(NCC4CCOCC4)C(=C3)[N+]([O-])=O)C(OC3=CN=C4NC=CC4=C3)=C2)=C(C1)C1=CC=C(Cl)C=C1

References

General References

Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. [Article]
Cang S, Iragavarapu C, Savooji J, Song Y, Liu D: ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol. 2015 Nov 20;8:129. doi: 10.1186/s13045-015-0224-3. [Article]
Salem AH, Agarwal SK, Dunbar M, Enschede SL, Humerickhouse RA, Wong SL: Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin's Lymphoma. J Clin Pharmacol. 2016 Aug 25. doi: 10.1002/jcph.821. [Article]
Agarwal SK, Hu B, Chien D, Wong SL, Salem AH: Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study. J Clin Pharmacol. 2016 Mar 7. doi: 10.1002/jcph.730. [Article]
Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG, Majewski IJ, Segal D, Heitner Enschede SL, Huang DC, Davids MS, Letai A, Roberts AW: The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016 Jun 23;127(25):3215-24. doi: 10.1182/blood-2016-01-688796. Epub 2016 Apr 11. [Article]
Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF: Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6. [Article]
King AC, Peterson TJ, Horvat TZ, Rodriguez M, Tang LA: Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies. Ann Pharmacother. 2017 May;51(5):410-416. doi: 10.1177/1060028016685803. Epub 2017 Jan 6. [Article]
Venetoclax, Safety Sheet [Link]
FDA Approved Drug Products: Venclexta (venetoclax) oral tablets [Link]
Australian Product Information: Venetoclax [File]
Venetoclax, Previous FDA label [File]

External Links

Human Metabolome Database: HMDB0247760
KEGG Drug: D10679
PubChem Compound: 49846579
PubChem Substance: 347827991
ChemSpider: 29315017
BindingDB: 60828
RxNav: 1747556
ChEBI: 133021
ChEMBL: CHEMBL3137309
ZINC: ZINC000150338755
PharmGKB: PA166153473
PDBe Ligand: LBM
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Venetoclax

PDB Entries

6o0k / 6o0l / 6o0m / 6o0p

FDA label

Download (1.31 MB)

MSDS

Download (230 KB)

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Available	Not Available	Acute Lymphoblastic Leukemia (ALL) / Acute Myeloid Leukemia / Amyloidosis / Chronic Lymphocytic Leukemia / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Plasma Cell Leukemia	1	somestatus	stop reason	just information to hide
Not Available	Available	Not Available	Relapsed Childhood ALL / Relapsed Childhood Lymphoblastic Lymphoma	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Cancer / Chronic Lymphocytic Leukemia	1	somestatus	stop reason	just information to hide
Not Available	No Longer Available	Not Available	Acute Lymphocytic Leukemia (ALL) / Lymphoblastic Lymphoma / Myelofibrosis	1	somestatus	stop reason	just information to hide
Not Available	Not Yet Recruiting	Not Available	Chronic Myeloid Leukemia (CML)	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Kit; tablet	Oral
Kit; tablet, film coated	Oral
Tablet	Oral	10 mg
Tablet	Oral	100 mg
Tablet	Oral	50 mg
Tablet, coated	Oral	10 mg
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	100 mg/1
Tablet, film coated	Oral	50 mg/1
Tablet, film coated	Oral	100.0 mg
Tablet, film coated	Oral	10.0 mg
Tablet, film coated	Oral	50.0 mg
Tablet, film coated	Oral
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	10 mg
Tablet, film coated	Oral	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9174982	No	2015-11-03	2030-05-26
US8546399	No	2013-10-01	2031-06-27
US9539251	No	2017-01-10	2033-09-06
US8722657	No	2014-05-13	2032-01-29
US10730873	No	2020-08-04	2031-11-21
US10993942	No	2021-05-04	2033-09-06
US11110087	No	2021-09-07	2033-09-06
US11369599	No	2012-05-23	2032-05-23
US11413282	No	2013-09-06	2033-09-06
US11590128	No	2013-09-06	2033-09-06

Properties

State

Solid

Experimental Properties

Property	Value	Source
logP	99	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.000933 mg/mL	ALOGPS
logP	6.92	ALOGPS
logP	6.76	Chemaxon
logS	-6	ALOGPS
pKa (Strongest Acidic)	4.19	Chemaxon
pKa (Strongest Basic)	7.96	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	10	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	172.03 Å²	Chemaxon
Rotatable Bond Count	12	Chemaxon
Refractivity	238.59 m³·mol^-1	Chemaxon
Polarizability	93.95 Å³	Chemaxon
Number of Rings	8	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	272.3913	predicted	DeepCCS 1.0 (2019)
[M+H]+	274.2867	predicted	DeepCCS 1.0 (2019)
[M+Na]+	280.43314	predicted	DeepCCS 1.0 (2019)

Targets

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

Details1. Apoptosis regulator Bcl-2

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells (PubMed:1508712, PubMed:8183370). Regulates cell death by controlling the mitochondrial membrane permeability (PubMed:11368354). Appears to function in a feedback loop system with caspases (PubMed:11368354). Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1) (PubMed:11368354). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function (PubMed:18570871, PubMed:20889974, PubMed:21358617). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785)
Specific Function: BH domain binding
Gene Name: BCL2
Uniprot ID: P10415
Uniprot Name: Apoptosis regulator Bcl-2
Molecular Weight: 26265.66 Da

References

Davids MS, Letai A: ABT-199: taking dead aim at BCL-2. Cancer Cell. 2013 Feb 11;23(2):139-41. doi: 10.1016/j.ccr.2013.01.018. [Article]
Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. [Article]
King AC, Peterson TJ, Horvat TZ, Rodriguez M, Tang LA: Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies. Ann Pharmacother. 2017 May;51(5):410-416. doi: 10.1177/1060028016685803. Epub 2017 Jan 6. [Article]
Castillo JJ, Treon SP: Management of Waldenstrom macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):372-379. doi: 10.1182/hematology.2020000121. [Article]
Pallis M, Burrows F, Ryan J, Grundy M, Seedhouse C, Abdul-Aziz A, Montero J, Letai A, Russell N: Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget. 2017 Mar 7;8(10):16220-16232. doi: 10.18632/oncotarget.8742. [Article]
Emadi A, Kapadia B, Bollino D, Bhandary B, Baer MR, Niyongere S, Strovel ET, Kaizer H, Chang E, Choi EY, Ma X, Tighe KM, Carter-Cooper B, Moses BS, Civin CI, Mahurkar A, Shetty AC, Gartenhaus RB, Kamangar F, Lapidus RG: Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia. 2021 Jul;35(7):1907-1924. doi: 10.1038/s41375-020-01080-6. Epub 2020 Nov 16. [Article]
Castillo JJ, Treon SP: What is new in the treatment of Waldenstrom macroglobulinemia? Leukemia. 2019 Nov;33(11):2555-2562. doi: 10.1038/s41375-019-0592-8. Epub 2019 Oct 7. [Article]
Wang L, Lin N: Double remission of chronic lymphocytic leukemia and secondary acute myeloid leukemia after venetoclax monotherapy: A case report. Medicine (Baltimore). 2021 Feb 12;100(6):e24703. doi: 10.1097/MD.0000000000024703. [Article]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Agarwal SK, Hu B, Chien D, Wong SL, Salem AH: Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study. J Clin Pharmacol. 2016 Mar 7. doi: 10.1002/jcph.730. [Article]
Weiss J, Gajek T, Kohler BC, Haefeli WE: Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. Pharmaceutics. 2016 Feb 24;8(1). pii: pharmaceutics8010005. doi: 10.3390/pharmaceutics8010005. [Article]
Freise KJ, Hu B, Salem AH: Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics. Eur J Clin Pharmacol. 2018 Apr;74(4):413-421. doi: 10.1007/s00228-017-2403-3. Epub 2018 Jan 4. [Article]
Venclexta FDA label [File]

Transporters

Details1. ATP-dependent translocase ABCB1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

Agarwal SK, Hu B, Chien D, Wong SL, Salem AH: Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study. J Clin Pharmacol. 2016 Mar 7. doi: 10.1002/jcph.730. [Article]
Australian Product Information, Venetoclax [File]
Venclexta FDA label [File]

Details2. Broad substrate specificity ATP-binding cassette transporter ABCG2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight: 72313.47 Da

References

Venclexta FDA label [File]
FDA label, Venclexta [File]

Details3. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Curator comments: Data supported only by in vitro evidence.

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

Weiss J, Gajek T, Kohler BC, Haefeli WE: Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. Pharmaceutics. 2016 Feb 24;8(1). pii: pharmaceutics8010005. doi: 10.3390/pharmaceutics8010005. [Article]
FDA label, Venclexta [File]

Drug created at April 18, 2016 16:22 / Updated at April 23, 2024 11:38

Venetoclax

Overview

Identification

Structure for Venetoclax (DB11581)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

Transporters

References

References

References