Peringatan Keamanan

Acute toxicity: oral toxicity (LD50) >2001 mg/kg (mouse) L4816.

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 FDA label.

Carcinogenicity studies have not yet been performed with venetoclax FDA 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 FDA label.

Venetoclax

DB11581

small molecule approved investigational

Deskripsi

Venetoclax is a BCL-2 inhibitor that was initially approved by the FDA in April 2016 FDA label. Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are important regulators of the apoptotic (programmed cell death) process A18565, A18566. Venetoclax is used to treat chronic lymphocytic leukemia (CLL) and certain types of small lymphocytic lymphoma FDA label. CLL is the most prevalent leukemia diagnosed in Western countries A40022. Venetoclax was developed through reverse engineering of the BCL-2 protein family inhibitor, navitoclax A40022. Venetoclax is approximately 10 times more potent than navitoclax with regard to induction of apoptosis in CLL cells A40022. 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 FDA label. Previously, this drug was indicated only for patients with 17p gene deletion F2130.

Struktur Molekul 2D

Berat 868.45
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life of venetoclax is reported to be 19-26 hours, after administration of a single 50-mg dose [A40022], [FDA label].
Volume Distribusi The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L [FDA label].
Klirens (Clearance) Mainly hepatic [FDA label].

Absorpsi

Following several oral administrations after a meal, the maximum plasma concentration of venetoclax was reached 5-8 hours after the dose A18567. 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 ?g/mL and AUC0-24 was 32.8 ± 16.9 ?g•h/mL at the 400 mg once daily dose FDA 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 A40022, FDA label.

Metabolisme

In vitro studies demonstrated that venetoclax is predominantly metabolized as a substrate of CYP3A4/5 FDA label, A18568, F2124.

Rute Eliminasi

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 FDA label.

Interaksi Makanan

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

Interaksi Obat

1092 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Venetoclax.
Modafinil The metabolism of Venetoclax can be increased when combined with Modafinil.
Armodafinil The metabolism of Venetoclax can be increased when combined with Armodafinil.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Venetoclax.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Venetoclax.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Venetoclax.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Venetoclax.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Venetoclax.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Venetoclax.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Venetoclax.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Venetoclax.
Silodosin The excretion of Silodosin can be decreased when combined with Venetoclax.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Venetoclax.
Brexpiprazole The metabolism of Brexpiprazole can be decreased when combined with Venetoclax.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Venetoclax.
Everolimus The metabolism of Everolimus can be decreased when combined with Venetoclax.
Flibanserin The metabolism of Flibanserin can be decreased when combined with Venetoclax.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Venetoclax.
Ivabradine The metabolism of Ivabradine can be decreased when combined with Venetoclax.
Ivacaftor The metabolism of Ivacaftor can be decreased when combined with Venetoclax.
Lurasidone The metabolism of Lurasidone can be decreased when combined with Venetoclax.
Olaparib The metabolism of Olaparib can be decreased when combined with Venetoclax.
Sonidegib The metabolism of Sonidegib can be decreased when combined with Venetoclax.
Avanafil The metabolism of Avanafil can be decreased when combined with Venetoclax.
Eplerenone The metabolism of Eplerenone can be decreased when combined with Venetoclax.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Venetoclax.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Venetoclax.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Venetoclax.
Fentanyl The metabolism of Fentanyl can be decreased when combined with Venetoclax.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Venetoclax.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Venetoclax.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Venetoclax.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Venetoclax.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Venetoclax.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Venetoclax.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Venetoclax.
Metreleptin The metabolism of Venetoclax can be increased when combined with Metreleptin.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Venetoclax.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Venetoclax.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Venetoclax.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Venetoclax.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Venetoclax.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Venetoclax.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Venetoclax.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Venetoclax.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Venetoclax.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Venetoclax.
Crizotinib The metabolism of Venetoclax can be decreased when combined with Crizotinib.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Venetoclax.
Eluxadoline The serum concentration of Eluxadoline can be increased when it is combined with Venetoclax.
Vincristine The excretion of Vincristine can be decreased when combined with Venetoclax.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Venetoclax.
Lumacaftor The serum concentration of Venetoclax can be decreased when it is combined with Lumacaftor.
Cobimetinib The metabolism of Cobimetinib can be decreased when combined with Venetoclax.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Venetoclax.
Vemurafenib The serum concentration of Venetoclax can be increased when it is combined with Vemurafenib.
Apalutamide The serum concentration of Venetoclax can be decreased when it is combined with Apalutamide.
Pitolisant The serum concentration of Venetoclax can be decreased when it is combined with Pitolisant.
Isavuconazole The serum concentration of Venetoclax can be increased when it is combined with Isavuconazole.
Isavuconazonium The serum concentration of Venetoclax can be increased when it is combined with Isavuconazonium.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Naringenin Naringenin may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Eltrombopag Eltrombopag may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Safinamide The metabolism of Safinamide can be decreased when combined with Venetoclax.
Teriflunomide Teriflunomide may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Cannabidiol The serum concentration of Venetoclax can be increased when it is combined with Cannabidiol.
Folic acid Venetoclax may decrease the excretion rate of Folic acid which could result in a higher serum level.
Allopurinol Venetoclax may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Celecoxib The metabolism of Celecoxib can be decreased when combined with Venetoclax.
Oxaliplatin Venetoclax may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
Fluorouracil Venetoclax may decrease the excretion rate of Fluorouracil which could result in a higher serum level.
Clofarabine Venetoclax may decrease the excretion rate of Clofarabine which could result in a higher serum level.
Nitrofurantoin Venetoclax may decrease the excretion rate of Nitrofurantoin which could result in a higher serum level.
Riluzole Venetoclax may decrease the excretion rate of Riluzole which could result in a higher serum level.
Tegaserod Venetoclax may decrease the excretion rate of Tegaserod which could result in a higher serum level.
Leflunomide Venetoclax may decrease the excretion rate of Leflunomide which could result in a higher serum level.
Alvocidib Venetoclax may decrease the excretion rate of Alvocidib which could result in a higher serum level.
Riociguat The metabolism of Riociguat can be decreased when combined with Venetoclax.
Fimasartan Venetoclax may decrease the excretion rate of Fimasartan which could result in a higher serum level.
Delafloxacin Venetoclax may decrease the excretion rate of Delafloxacin which could result in a higher serum level.
Nabiximols The metabolism of Nabiximols can be decreased when combined with Venetoclax.
Caffeine Caffeine may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Dronabinol The serum concentration of Dronabinol can be increased when it is combined with Venetoclax.
Pantoprazole The metabolism of Pantoprazole can be decreased when combined with Venetoclax.
Estradiol The metabolism of Estradiol can be decreased when combined with Venetoclax.
Telmisartan Telmisartan may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Quercetin Quercetin may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Vismodegib Vismodegib may decrease the excretion rate of Venetoclax which could result in a higher serum level.
Conjugated estrogens The metabolism of Conjugated estrogens can be decreased when combined with Venetoclax.
Prazosin Venetoclax may decrease the excretion rate of Prazosin which could result in a higher serum level.
Zidovudine The metabolism of Zidovudine can be decreased when combined with Venetoclax.
Sumatriptan Venetoclax may decrease the excretion rate of Sumatriptan which could result in a higher serum level.
Mycophenolate mofetil The metabolism of Mycophenolate mofetil can be decreased when combined with Venetoclax.
Lamivudine Venetoclax may decrease the excretion rate of Lamivudine which could result in a higher serum level.
Donepezil The metabolism of Donepezil can be decreased when combined with Venetoclax.
Ezetimibe Venetoclax may decrease the excretion rate of Ezetimibe which could result in a higher serum level.
Camptothecin Venetoclax may decrease the excretion rate of Camptothecin which could result in a higher serum level.

Target Protein

Apoptosis regulator Bcl-2 BCL2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 23291630
    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.
  • PMID: 26589495
    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.
  • PMID: 27558232
    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.
  • PMID: 26953185
    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.
  • PMID: 27069256
    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.
  • PMID: 26639348
    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.
  • PMID: 28056525
    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.

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