Venetoclax
 | |
| Clinical data | |
|---|---|
| Trade names | Venclexta |
| Routes of administration | Oral (tablets) |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Protein binding | >99.9%[1] |
| Metabolism | Hepatic (CYP3A4, CYP3A5) |
| Onset of action | Tmax = 5–8 hours |
| Biological half-life | ~26 hours |
| Excretion | Feces (>99.9%; 20.8% as unchanged venetoclax) |
| Identifiers | |
| |
| CAS Number | 1257044-40-8 |
| PubChem (CID) | 49846579 |
| ChemSpider | 29315017 |
| KEGG | D10679 |
| ChEBI |
CHEBI:133021  |
| Chemical and physical data | |
| Formula | C45H50ClN7O7S |
| Molar mass | 868.44 g/mol |
| 3D model (Jmol) | Interactive image |
| |
| |
Venetoclax (INN,[2] trade name Venclexta ven-KLEKS-tuh,[1] previously known as GDC-0199, ABT-199, and RG7601)[3] is a small molecule oral drug that treats chronic lymphocytic leukemia (CLL) in those with a specific chromosomal abnormality.[4] In 2015, the United States Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to venetoclax for subjects with CLL who have relapsed or have been refractory to previous treatment and have the 17p deletion genetic mutation.
Medical use
Venetoclax is used a second line treatment for chronic lymphocytic leukemia, only if there is a 17p deletion as determined by an approved test.[1]
Side Effects
Common side effects of venetoclax include neutropenia (low white blood cell count), nausea, anemia, diarrhea, upper respiratory tract infection, fatigue, and thrombocytopenia (low platelet count). Major side effects include tumor lysis syndrome and severe neutropenia. Additionally, this drug may cause fertility problems in males.[1]
Pharmacology
Mechanism of action
Venetoclax is a BH3-mimetic and acts as a Bcl-2 inhibitor. It blocks this anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells. Overexpression of Bcl-2 in some lymphoid malignancies has sometimes shown to be linked with increased resistance to chemotherapy.[5]
Pharmacokinetics
The maximum plasma concentration achieved after oral administration occurred 5-8 hours after dose.[1] Steady state maximum concentration with low-fat meal conditions at the 400 mg once daily dose was found to be 2.1 ± 1.1 ug/mL. It is recommended that Venetoclax be administered with a meal.[1]
The apparent Volume of Distribution for Venetoclax is approximately 256-321 L. It is highly bound to human plasma protein. Within a concentration range of 1-30 μM (0.87-26 μg/mL), the fraction unbound in plasma was less than 0.01.[1]
Venetoclax is metabolized by CYP3A4/5 as proven by in-vitro studies.[1] Those using the drug should not consume grapefruit products because they contain CYP3A inhibitors.[1] Additionally, while using venetoclax it is not recommended to use other drugs which contain CYP3A inhibitors (i.e: erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil.)[1] Venetoclax is excreted from the body via the fecal route.[1]
History
On April 11, 2016, the FDA approved venetoclax for use in those with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy.[1][4] Based on overall response rate, the indication was approved under accelerated FDA approval.[1]
In October 2016 a European Medicines Agency committee recommended provisional marketing approval for venetoclax for CLL; the drug had already been granted orphan status in 2012 for that use.[6]
Society and culture
Abbvie Inc. of North Chicago Illinois manufactures Venclexta.[7] It is marketed by both Abbvie Inc. and Genentech USA Inc. of South San Francisco, California, which is a member of the Roche Group.[7] AbbVie and Genentech are both commercializing the drug within the United States, but only AbbVie has rights to do so outside of the U.S.[8]
According to Reuters 2016 Drugs to Watch, the 2020 forecast sales for Venetoclax are 1.48 billion.[9] Competition is expected from other drugs such as Imbruvica (ibrutinib) and Zydelig (idelalisib), both of which were also approved in 2014 to treat CLL (chronic lymphocytic leukemia).[9][10]
Venclexta patented by Abbvie Inc. US Patent: 9,174,982.[11]
Research
As of 2016 venetoclax had been tested to treat other hematological cancers, including non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma and follicular lymphoma.[12]
References
- 1 2 3 4 5 6 7 8 9 10 11 12 13 "US Venetoclax label" (PDF). FDA. April 2016.
- ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed International Nonproprietary Names: List 111" (PDF). WHO Drug Information. 28 (2): 270. 2014. Retrieved 14 April 2016.
- ↑ "Venetoclax". AdisInsight. Retrieved 21 November 2016.
- 1 2 "FDA Approves New Drug for Chronic Lymphocytic Leukemia in Patients with a Specific Chromosomal Abnormality". U.S. Food and Drug Administration. Retrieved 14 April 2016.
- ↑ "Center for Drug Evaluation and Research - Application 208573Orig1s000 - Division Director Summary Review" (PDF). Food and Drug Administration (FDA). Retrieved 21 Nov 2016.
- ↑ "CHMP summary of positive opinion for Venclyxto". European Medicines Agency. Retrieved 21 November 2016.
- 1 2 "Press Announcements - FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality". www.fda.gov. Retrieved 2016-11-16.
- ↑ "Inside the development of Venclexta, AbbVie's new leukemia drug". BioPharma Dive. Retrieved 2016-11-16.
- 1 2 "Drugs to Watch 2016 - Thomas Reuters" (PDF). Retrieved 16 Nov 2016.
- ↑ "Ibrutinib and Idelalisib Continue to Impress in CLL, May Eventually Replace Chemotherapy for Some Patients". OncLive. Retrieved 2016-11-17.
- ↑ "United States Patent: 9174982". patft.uspto.gov. Retrieved 2016-11-21.
- ↑ "Drugs to Watch 2016 - Market Insight Report" (PDF). Thomson Reuters. Retrieved 16 Nov 2016.