Voxelotor
Voxelotor Uses, Dosage, Side Effects, Food Interaction and all others data.
Voxelotor is a novel hemoglobin S polymerization inhibitor for the treatment of sickle cell disease. This is a genetically inherited condition most prevalent in the Middle East, Africa, and certain parts of India. Sickle cell disease can lead to excruciating pain, stroke, infection, and various other complications arising from the blockage of blood vessels.
Voxelotor was granted accelerated FDA approval on November 25 2019, as it likely to be a promising treatment for the 100,000 individuals in the U.S. suffering from the disease, in addition to 20 million others worldwide. It was developed by Global Blood Therapeutics, Inc. and is unique from other drugs used to treat sickle cell anemia, such as hydroxyurea, L-glutamine, and crizanlizumab due to its novel mechanism of action.
Voxelotor modifies hemoglobin to prevent painful and dangerous sickle cell crises that normally lead to organ damage, hospitalization, and sometimes death. It prevents low hemoglobin, which is normally associated with the destruction of sickled blood cells in sickle cell disease. Voxelotor has led to up to a 40% increase in hemoglobin in clinical trials.
| Trade Name | Voxelotor |
| Availability | Prescription only |
| Generic | Voxelotor |
| Voxelotor Other Names | Voxelotor, Voxélotor, Voxelotorum |
| Related Drugs | hydroxyurea, vitamin e, Hydrea, Endari, glutamine, Adakveo |
| Weight | 500mg |
| Type | Oral tablet |
| Formula | C19H19N3O3 |
| Weight | Average: 337.379 Monoisotopic: 337.142641484 |
| Protein binding | The protein binding of voxeletor is 99.8%, according to in vitro studies. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Voxelotor is a drug used to inhibit the polymerization of hemoglobin S, preventing the painful and sometimes lethal vaso-occlusive crises associated with sickle cell disease.
Voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 12 years and above.
Voxelotor is also used to associated treatment for these conditions: Sickle Cell Disease (SCD)
How Voxelotor works
Deoxygenated sickle hemoglobin (HbS) polymerization is the causal factor for sickle cell disease. The genetic mutation associated with this disease leads to the formation of abnormal, sickle shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Voxelotor binds irreversibly with the N‐terminal valine of the α‐chain of hemoglobin, leading to an allosteric modification of Hb20, which increases the affinity for oxygen. Oxygenated HbS does not polymerize. By directly blocking HbS polymerization, voxelotor can successfully treat sickle cell disease by preventing the formation of abnormally shaped cells, which eventually cause lack of oxygenation and blood flow to organs.
Toxicity
LD50 information and overdose information is unavailable at this time. Dose-limiting toxicities are unlikely, based on the results of clinical studies.
Food Interaction
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of voxelotor.
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of voxelotor.
- Take with or without food.
[Moderate] MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.
Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).
In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.
Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.
Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.
MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4.
Grapefruit and grapefruit juice should be avoided if an interaction is suspected.
Orange juice is not expected to interact with these drugs.
Voxelotor Disease Interaction
Volume of Distribution
The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma.
Elimination Route
Voxelotor is rapidly absorbed after oral administration, with a plasma Tmax of 2 hours. Tmax in the red blood cells ranges from 17-24 hours. The Cmax, on average in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high fat meal with voxelotor significantly increased exposure to the drug during clinical trials. After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 μg*h mL−1, respectively.
Half Life
The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours, according to the FDA label. The mean half-life in the red blood cell is 60 days. The average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy patients, in one clinical study.
Clearance
The apparent oral clearance of voxelotor is approximately 6.7 L/h.
Elimination Route
62.6% of the voxelotor dose administered orally as well as its metabolites are found in the feces (with 33.3% as unchanged drug) and 35.5% in urine (with only 0.08% unchanged drug).
Innovators Monograph
You find simplified version here Voxelotor
