Voxelotor

Breast Feeding; Lactation; Milk, Human; Hematologic Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Warning

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P273, P301+P317, P330, P391, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In clinical trials of voxelotor in patients with sickle cell disease, serum aminotransferase elevations occurred in 1% to 2% of patients during therapy, but the elevations were usually asymptomatic, self-limited in course and mild-to-moderate in degree. Patients with sickle cell disease frequently have liver test abnormalities and most have some degree of jaundice, due largely to hemolysis. They are also at risk for gall stone disease (from chronic hemolysis), chronic hepatitis B and C (from blood transfusions), iron overload (from frequent transfusions), congestive liver disease (due to pulmonary hypertension), and veno-occlusive crises involving the liver which can be associated with serum aminotransferase elevations. In preregistration trials of voxelotor, hepatic events were no more common with the active drug than with placebo. Rare instances of acute aminotransferase elevations of unknown cause occurred in patients receiving voxelotor, but were self-limited in course and were not associated with worsening of preexisting bilirubin elevations or need for dose modification or discontinuation.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Voxelotor

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation

◈ What is voxelotor?

B - Blood and blood forming organs

QB - Blood and blood forming organs

Voxelotor increases hemoglobin (Hb) oxygen affinity in a dose-dependent manner. It has led to up to a 40% increase in hemoglobin in clinical trials. Voxelotor may inhibit red blood cell sickling, attenuate red blood cell deformability, and reduce whole blood viscosity.

Sickle cell disease is characterized by deoxygenated sickle hemoglobin (HbS) polymerization. The genetic mutation causing 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. Sickle-shaped red blood cells cannot effectively bind oxygen, thus incapable of allowing normal blood flow to organs. Voxelotor increases Hb oxygen affinity. It binds reversibly to hemoglobin (Hb) by forming a covalent bond with the N‐terminal valine of the α‐chain of the protein, resulting in an allosteric modification of Hb. Voxelotor stabilizes the oxygenated Hb state and prevents HbS polymerization by increasing hemoglobin’s affinity for oxygen.

The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours. The mean half-life in the red blood cell is 60 days. In one study, the average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy subjects.

Voxeletor is heavily metabolized via two phases. Phase I metabolism consists of oxidation and reduction, while phase II metabolism consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4 and by CYP2C19, CYP2B6, and CYP2C9, to a lesser extent.

3ZO554A4Q8

VOXELOTOR

Established Pharmacologic Class [EPC] - Hemoglobin S Polymerization Inhibitor

Mechanisms of Action [MoA] - Hemoglobin S Polymerization Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Voxelotor is a Hemoglobin S Polymerization Inhibitor. The mechanism of action of voxelotor is as a Hemoglobin S Polymerization Inhibitor and Cytochrome P450 3A4 Inhibitor.

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 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.

About 62.6% of the oral dose is found in the feces, of which 33.3% is an unchanged drug. About 35.5% of the dose is recovered in urine, with only 0.08% as the unchanged drug.

The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma.

The apparent oral clearance of voxelotor is approximately 6.7 L/h.