Identification

Name
Venetoclax
Accession Number
DB11581
Type
Small Molecule
Groups
Approved, Investigational
Description

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 [10].

Structure
Thumb
Synonyms
  • 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
  • Venetoclax
External IDs
ABT 199 / ABT-199 / ABT199 / GDC-0199 / GDC0199 / RG-7601 / RG7601
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VenclextaTablet10 mgOralAbbvie2016-10-31Not applicableCanada
VenclextaTablet, film coated10 mg/1OralAbbVie Inc.2016-04-11Not applicableUs
VenclextaTablet100 mgOralAbbvie2016-10-31Not applicableCanada
VenclextaTablet, film coated100 mg/1OralAbbVie Inc.2016-04-11Not applicableUs
VenclextaTablet50 mgOralAbbvie2016-10-31Not applicableCanada
VenclextaTablet, film coated50 mg/1OralAbbVie Inc.2016-04-11Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
VenclextaVenetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)Kit; TabletOralAbbvie2016-10-31Not applicableCanada
VenclextaVenetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)KitAbbVie Inc.2016-04-11Not applicableUs
VenclextaVenetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)Kit; TabletOralAbbvie2016-10-31Not applicableCanada
VenclextaVenetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)KitAbbVie Inc.2016-04-11Not applicableUs
VenclextaVenetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)KitAbbVie Inc.2016-04-11Not applicableUs
VenclextaVenetoclax (10 mg) + Venetoclax (50 mg) + Venetoclax (100 mg)Kit; TabletOralAbbvie2016-10-31Not applicableCanada
VenclextaVenetoclax (10 mg/1) + Venetoclax (50 mg/1) + Venetoclax (100 mg/1) + Venetoclax (100 mg/1)KitAbbVie Inc.2016-04-11Not applicableUs
Categories
UNII
N54AIC43PW
CAS number
1257044-40-8
Weight
Average: 868.45
Monoisotopic: 867.3180959
Chemical Formula
C45H50ClN7O7S
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

Pharmacology

Indication

A BCL-2 inhibitor indicated for the treatment of 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].

Associated Conditions
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].

TargetActionsOrganism
AApoptosis regulator Bcl-2
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], [9].

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].

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Venetoclax.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Venetoclax.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Venetoclax.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Venetoclax.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Venetoclax.
6-Deoxyerythronolide BThe metabolism of Venetoclax can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Venetoclax.
7-ethyl-10-hydroxycamptothecinThe metabolism of 7-ethyl-10-hydroxycamptothecin can be decreased when combined with Venetoclax.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Venetoclax.
AbataceptThe metabolism of Venetoclax can be increased when combined with Abatacept.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:23291630]
  2. 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. [PubMed:26589495]
  3. 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. [PubMed:27558232]
  4. 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. [PubMed:26953185]
  5. 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. [PubMed:27069256]
  6. 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. [PubMed:26639348]
  7. 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. [PubMed:28056525]
  8. Venetoclax, Safety Sheet [Link]
  9. Australian Product Information: Venetoclax [File]
  10. Venetoclax, Previous FDA label [File]
External Links
KEGG Drug
D10679
PubChem Compound
49846579
PubChem Substance
347827991
ChemSpider
29315017
BindingDB
60828
ChEBI
133021
ChEMBL
CHEMBL3137309
PharmGKB
PA166153473
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Venetoclax
ATC Codes
L01XX52 — Venetoclax
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (1.31 MB)
MSDS
Download (230 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentMalignant Lymphomas / Mantle Cell Lymphoma (MCL)1
1Active Not RecruitingTreatmentCancer, Advanced / Cancer, Breast / Leukemia Acute Myeloid Leukemia (AML) / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancer Small Cell Lung Cancer (SCLC) / Malignancies / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Prostate Cancer1
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)2
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia, Prolymphocytic / Small Lymphocytic Lymphoma (SLL)1
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Non-Hodgkin's Lymphoma (NHL)1
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
1Active Not RecruitingTreatmentFollicular Lymphoma (FL)1
1Active Not RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
1Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)2
1Active Not RecruitingTreatmentRelapsed/Refractory Multiple Myeloma1
1CompletedBasic ScienceNon-Hodgkin's Lymphoma (NHL)1
1CompletedTreatmentLupus Erythematosus1
1Not Yet RecruitingBasic ScienceMalignancies, Hematologic1
1Not Yet RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Chronic Lymphocytic Leukemia (CLL) - Refractory / Relapsed Chronic Lymphocytic Leukemia1
1Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)3
1RecruitingOtherFollicular Lymphoma (FL) / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentAL Amyloidosis1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemia Acute Myeloid Leukemia (AML) / Malignancies / Neuroblastomas / Non-Hodgkin's Lymphoma (NHL) / Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) / Relapsed or Refractory Acute Myeloid Leukemia (AML) / Relapsed or Refractory Malignancies / Relapsed or Refractory Neuroblastoma / Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) / Relapsed or Refractory Tumors That Expresses B Cell Lymphoma 2 (BCL-2)1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Lymphoma, Lymphoblastic1
1RecruitingTreatmentAdvanced Solid Tumors Cancer / Malignancies, Hematologic / Tumors, Solid1
1RecruitingTreatmentB-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma / Grade 1 Follicular Lymphoma / Grade 2 Follicular Lymphoma / Grade 3a Follicular Lymphoma / Recurrent Burkitt Lymphoma / Recurrent Diffuse Large B-Cell Lymphoma / Recurrent Follicular Lymphoma / Recurrent Marginal Zone Lymphoma / Refractory Burkitt Lymphoma / Refractory Diffuse Large B Cell Lymphoma / Refractory Follicular Lymphoma / Transformed Recurrent Non-Hodgkin Lymphoma1
1RecruitingTreatmentBlastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)1
1RecruitingTreatmentBurkitt's Lymphoma / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Malignant Lymphomas / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentCancer - Acute Myeloid Leukemia / Cancer - Acute Myeloid Leukemia (AML) / Leukemia Acute Myeloid Leukemia (AML)1
1RecruitingTreatmentCancer - Acute Myeloid Leukemia / Leukemia Acute Myeloid Leukemia (AML)1
1RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
1RecruitingTreatmentChronic Myelomonocytic Leukemia (CMML) / Hematopoietic Stem Cell Transplant (HSCT) / Leukemia Acute Myeloid Leukemia (AML) / MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable) / Myelodysplastic Syndromes (MDS)1
1RecruitingTreatmentHigh Grade B-cell Lymphoma / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
1RecruitingTreatmentHigh-grade B-cell Lymphoma / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
1RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)2
1RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentLeukemias2
1RecruitingTreatmentMantle Cell Lymphoma (MCL)1
1RecruitingTreatmentMantle Cell Lymphoma (MCL) / Recurrent Lymphoma, Mantle-Cell1
1RecruitingTreatmentMultiple Myeloma (MM)1
1RecruitingTreatmentMyelodysplastic Syndromes (MDS)1
1RecruitingTreatmentMyelodysplastic Syndromes (MDS) / Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)1
1RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)2
1RecruitingTreatmentRefractory Diffuse Large B Cell Lymphoma / Relapsed, Diffuse Large B-cell Lymphoma1
1RecruitingTreatmentRelapsed or Refractory Chronic Lymphocytic Leukemia (CLL)1
1WithdrawnBasic ScienceNon-Hodgkin's Lymphoma (NHL)1
1WithdrawnBasic ScienceRelapsed/Refractory Non-Hodgkin's Lymphoma1
1WithdrawnTreatmentChronic Lymphocytic Leukaemia (CLL) / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma (SLL)1
1WithdrawnTreatmentLeukemia, Lymphocytic, Chronic, B-Cell1
1, 2Active Not RecruitingTreatmentAcute Myelogenous Leukaemia (AML) / Leukemia Acute Myeloid Leukemia (AML)1
1, 2Active Not RecruitingTreatmentAcute Myelogenous Leukaemia (AML) / Myelogenous Leukemia / Treatment Naive AML1
1, 2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Chronic Lymphocytic Leumemia / Chronic Lymphocytic Leumemia (CLL) / Leukemia Acute Myeloid Leukemia (AML) / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma (SLL)1
1, 2Active Not RecruitingTreatmentDouble-expressor Lymphoma (DEL) / Double-hit Lymphoma (DHL) / High-grade B-cell Lymphoma (HGBL) / Malignant Lymphomas / Multiple Myeloma (MM) / Refractory Diffuse Large B-cell Lymphoma (DLBCL) / Refractory Lymphomas / Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) / Relapsed and/or Refractory Lymphoma / Relapsed Ddiffuse Large B-Cell Lymphoma (DLBCL) / Relapsed Lymphomas / Triple-hit Lymphoma (THL)1
1, 2Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
1, 2Not Yet RecruitingTreatmentAtypical Chronic Myeloid Leukemia, BCR-ABL1 Negative / Chronic Eosinophilic Leukemia, Not Otherwise Specified / Chronic Myelomonocytic Leukemia / Chronic Neutrophilic Leukemia / Dysplasia / Essential Thrombocythemia (ET) / FGFR1 Gene Rearrangement / Leukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome / Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis / Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable / Myeloid Neoplasm / Myeloproliferative Neoplasm, Unclassifiable / Myeloproliferative Neoplasms / Overt Primary Myelofibrosis / PDGFRA Gene Rearrangement / PDGFRB Gene Rearrangement / Polycythemia Vera (PV) / Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase / Prefibrotic/Early Primary Myelofibrosis1
1, 2Not Yet RecruitingTreatmentCastration Levels of Testosterone / Castration-Resistant Prostate Carcinoma / Metastatic Hormone Refractory Prostate Cancer / Metastatic Prostate Carcinoma in the Soft Tissue / Prostate Carcinoma Metastatic in the Bone / PSA Progression / Stage IV Prostate Cancer AJCC v8 / Stage IVA Prostate Cancer AJCC v8 / Stage IVB Prostate Cancer AJCC v81
1, 2Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Relapsed Adult AML1
1, 2Not Yet RecruitingTreatmentRecurrent B Acute Lymphoblastic Leukemia / Recurrent T Acute Lymphoblastic Leukemia / Refractory B Acute Lymphoblastic Leukemia / Refractory T Acute Lymphoblastic Leukemia1
1, 2Not Yet RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma / T(11;14) Negative1
1, 2Not Yet RecruitingTreatmentRelapsed Non Hodgkin Lymphoma1
1, 2Not Yet RecruitingTreatmentRelapsed Refractory Multiple Myeloma1
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemia Recurrent / Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Leukemias / Philadelphia Chromosome Positive / Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Refractory Acute Lymphoblastic Leukemia / Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive / T(9;22)1
1, 2RecruitingTreatmentAcute Myeloid Leukemia With FLT3/ITD Mutation / Acute, recurrent Myeloid Leukemia / FLT3 Gene Mutation / FLT3 Internal Tandem Duplication / Refractory Acute Leukemia1
1, 2RecruitingTreatmentAdvanced Hematologic Malignancies / Leukemia Acute Myeloid Leukemia (AML) / Other Diseases of Blood and Blood-Forming Organs1
1, 2RecruitingTreatmentB Acute Lymphoblastic Leukemia / Lymphoblasts 5 Percent or More of Bone Marrow Nucleated Cells / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Lymphoblastic Leukemia / Refractory Acute Lymphoblastic Leukemia / T Acute Lymphoblastic Leukemia1
1, 2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)2
1, 2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Chronic Lymphocytic Leukemia (CLL) - Refractory1
1, 2RecruitingTreatmentFollicular Lymphoma (FL) / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
1, 2RecruitingTreatmentHematopoietic Cell Transplantation Recipient / Recurrent Diffuse Large B-Cell Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Marginal Zone Lymphoma / Recurrent Non-Hodgkin Lymphoma / Refractory Diffuse Large B Cell Lymphoma / Refractory Follicular Lymphoma / Refractory Marginal Zone Lymphoma / Refractory Non-Hodgkin's lymphoma / Refractory Transformed Indolent Non-Hodgkin Lymphoma1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Other Diseases of Blood and Blood-Forming Organs1
1, 2RecruitingTreatmentMantle Cell Lymphoma (MCL)1
1, 2RecruitingTreatmentMultiple Myeloma (MM)1
1, 2RecruitingTreatmentMultiple Myeloma (MM) / Relapsed/Refractory Multiple Myeloma1
1, 2RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma1
1, 2RecruitingTreatmentRefractory Follicular Lymphoma / Relapsed Follicular Lymphoma1
1, 2SuspendedTreatmentRecurrent Plasma Cell Myeloma / T(11;14)1
2Active Not RecruitingTreatment17 p Deletion / Cancer of the Blood and Bone Marrow / Chronic Lymphocytic Leukaemia (CLL)1
2Active Not RecruitingTreatmentChronic Lymphocytic Leucemia1
2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)2
2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Chronic Lymphocytic Leukemia (CLL) - Refractory / Chronic, recurrent Lymphocytic Leukemia / Leukemias / Recurrent Small Lymphocytic Lymphoma / Refractory Small Lymphocytic Lymphoma / Small Lymphocytic Lymphoma (SLL) / Untreated Chronic Lymphocytic Leukemia / Untreated Small Lymphocytic Lymphoma1
2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia, Lymphocytic, Chronic, B-Cell / Small Lymphocytic Lymphoma (SLL)1
2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
2Active Not RecruitingTreatmentWaldenström's Macroglobulinemia (WM)1
2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Leukemia Acute Myeloid Leukemia (AML)1
2CompletedTreatmentFollicular Lymphoma (FL) / Relapsed or Refractory Follicular Lymphoma1
2Not Yet RecruitingTreatmentCD20 Positive / Mantle Cell Lymphoma (MCL)1
2Not Yet RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)3
2Not Yet RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Ibrutinib Resistance1
2Not Yet RecruitingTreatmentChronic Myeloid Leukemia (CML)1
2Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2Not Yet RecruitingTreatmentMantle Cell Lymphoma (MCL)1
2Not Yet RecruitingTreatmentMultiple Myeloma (MM)1
2RecruitingTreatmentCancer - Multiple Myeloma / Multiple Myeloma (MM)1
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)4
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemias / Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)1
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Primary Lymphoid Haematopoietic Neoplasms / Small Lymphocytic Lymphoma (SLL)1
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Leukemia (SLL)1
2RecruitingTreatmentChronic Lymphocytic Leukemia (CLL) - Refractory / Chronic, recurrent Lymphocytic Leukemia / Recurrent Small Lymphocytic Lymphoma / Refractory Small Lymphocytic Lymphoma1
2RecruitingTreatmentChronic Chronic myelogenous leukemia / Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia1
2RecruitingTreatmentEstrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer1
2RecruitingTreatmentFollicular Lymphoma (FL) / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Marginal Zone Lymphoma / Mucosa Associated Lymphoid Tissue1
2RecruitingTreatmentFollicular Lymphoma (FL) / Non-Hodgkin's Lymphoma Follicular / Non-Hodgkin's Lymphoma, Adult High Grade1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)3
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome / Other Diseases of Blood and Blood-Forming Organs1
2RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
2RecruitingTreatmentMantle Cell Lymphoma (MCL)2
2RecruitingTreatmentMultiple Myeloma (MM)1
2RecruitingTreatmentMultiple Myeloma (MM) / Relapsed Or Refractory Multiple Myeloma1
2RecruitingTreatmentRecurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma / Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma1
2RecruitingTreatmentAcute, recurrent Myeloid Leukemia / Refractory Acute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
2RecruitingTreatmentRecurrent Cutaneous T-cell lymphoma / Refractory T-Cell Lymphoma1
2RecruitingTreatmentRichter's Syndrome1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)4
3Active Not RecruitingTreatmentRelapsed/Refractory Multiple Myeloma1
3Not Yet RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Chronic Lymphocytic Leukaemia (CLL) / Leukemia Acute Myeloid Leukemia (AML) / Malignancies / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
3Not Yet RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
3RecruitingTreatmentCCND1 Negative / CCND1/IGHG1 Fusion Negative / Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL) / T(11;14) Negative1
3RecruitingTreatmentCancer - Chronic Lymphocytic Leukemia / Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
3RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)2
3RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)2
3RecruitingTreatmentLeukemia, Lymphocytic, Chronic, B-Cell1
3RecruitingTreatmentMantle Cell Lymphoma (MCL)1
3RecruitingTreatmentMultiple Myeloma (MM)1
Not AvailableAvailableNot AvailableAcute Lymphoblastic Leukaemias (ALL) / Amyloidosis / Chronic Chronic myelogenous leukemia / Chronic Lymphocytic Leukaemia (CLL) / Leukemia Acute Myeloid Leukemia (AML) / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
Not AvailableRecruitingNot AvailableLeukemia Acute Myeloid Leukemia (AML)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit
Kit; tabletOral
TabletOral10 mg
TabletOral100 mg
TabletOral50 mg
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9174982No2015-11-032030-05-26Us
US8546399No2013-10-012031-06-27Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP99MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.000933 mg/mLALOGPS
logP6.92ALOGPS
logP6.76ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)4.19ChemAxon
pKa (Strongest Basic)7.96ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area172.03 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity238.59 m3·mol-1ChemAxon
Polarizability93.95 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Aminobenzenesulfonamides / Diarylethers / Aminobenzoic acids and derivatives / Pyrrolopyridines / Benzenesulfonyl compounds / Nitrobenzenes / Aniline and substituted anilines / Benzoyl derivatives / Dialkylarylamines
show 26 more
Substituents
Phenylpiperazine / N-arylpiperazine / Diaryl ether / Aminobenzenesulfonamide / Benzenesulfonamide / Aminobenzoic acid or derivatives / Benzenesulfonyl group / Pyrrolopyridine / Nitrobenzene / Benzoic acid or derivatives
show 52 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appea...
Gene Name
BCL2
Uniprot ID
P10415
Uniprot Name
Apoptosis regulator Bcl-2
Molecular Weight
26265.66 Da
References
  1. 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. [PubMed:23410971]
  2. 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. [PubMed:23291630]
  3. 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. [PubMed:28056525]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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. [PubMed:26953185]
  2. 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. [PubMed:26927160]
  3. 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. [PubMed:29302721]
  4. Venclexta FDA label [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. 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. [PubMed:26953185]
  2. Australian Product Information, Venetoclax [File]
  3. Venclexta FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Venclexta FDA label [File]
  2. FDA label, Venclexta [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Data supported only by in vitro evidence.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. 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. [PubMed:26927160]
  2. FDA label, Venclexta [File]

Drug created on April 18, 2016 10:22 / Updated on March 22, 2019 03:18