Vadadustat - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

The U.S. Food and Drug Administration (FDA) authorized Vadadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), on March 27, 2024, for the treatment of anemia (low red blood cell count) caused by chronic kidney disease (CKD) in individuals on dialysis (a therapy used to remove excess fluid and waste materials from the blood) for a minimum of three months. In this condition, kidney function deteriorates over time. The approval was predicated on post-marketing safety data from Japan, where Vadadustat was introduced in August 2020, as well as efficacy and safety data from the INNO2VATE program. For the millions of Americans on dialysis, it is an alternative course of therapy.

Drug Group

Vadadustat is categorized as a hypoxia-inducible factor prolyl hydroxylase inhibitor drug. These substances promote the synthesis of endogenous erythropoietin, which raises the production of hemoglobin and red blood cells to control anemia.

Indications

Vadadustat is prescribed to people with chronic kidney disease (CKD) who have been on dialysis for a minimum of three months to cure anemia.

Restrictions on Use

• Vadadustat has not improved fatigue, quality of life, or patient satisfaction.

• Vadadustat is not recommended for use in the following situations:

  • Patients who need red blood cell transfusions to treat anemia right away.

  • In CKD patients without dialysis who have anemia.

Contraindications

• Patients who have a history of recognized hypersensitivity (allergic reaction) to Vadadustat or any of its constituents should not use Vadadustat.

• Vadadustat should be contraindicated in patients with uncontrolled hypertension (high blood pressure).

Dosage Forms and Available Strengths

There are three dosages for Vadadustat tablets:

• 150 mg (milligrams).

• 300 mg.

• 450 mg.

Warnings and Precautions

• Hepatotoxicity: Patients taking Vadadustat have been known to develop hepatotoxicity (liver damage). Before and for the first six months following start-up, measure ALT (alanine transaminase), AST (aspartate transaminase), and bilirubin monthly, and then as directed by a physician. If the ALT or AST are consistently high or are increasing along with the bilirubin, stop taking Vadadustat.

• Hypertension: It is critical to monitor blood pressure and modify anti-hypertensive medication as necessary because hypertension can worsen and could result in a hypertensive crisis.

• Seizures: Vadadustat-using patients with CKD have been documented to experience seizures (uncontrolled electrical activity in the brain); therefore, it is essential to monitor for any spikes in seizure frequency, premonitory signs, or new-onset seizures.

• Gastrointestinal Erosion: Vadadustat has been reported to have gastric or esophageal erosions and gastrointestinal bleeding.

• Malignancy: Vadadustat is not advised for those with active cancer since it may have a detrimental effect on the progress of the cancer.

For Patients

What Is Anemia Due to Chronic Kidney Disease?

One typical complication of chronic kidney disease (CKD) is anemia. The kidneys produce Erythropoietin, a hormone that causes the bone marrow to create red blood cells. Red blood cell formation may decline in chronic kidney disease (CKD) due to a decrease in this hormone produced by the kidneys. Patients with CKD have shorter red blood cell lives. Furthermore, anemia frequently results in dietary deficiencies, including iron, folate, and vitamin B12. Kidney failure's toxic side effect, uremia (high urea levels in the blood), can damage marrow precursor cells and reduce erythropoiesis (the process of producing red blood cells). Poor platelet function, capillary fragility, repeated blood tests, and dialysis can all contribute to significant blood loss in patients with chronic kidney disease (CKD). Decreased food consumption, iron absorption, and utilization can also result in anemia.

How Does Vadadustat Work?

The hormone erythropoietin, which stimulates the synthesis of red blood cells, is produced when Vadadustat inhibits the enzyme hypoxia-inducible factor prolyl hydroxylase (HIF-PH), increasing the activity of HIFs. Increased iron mobilization, a slow increase in hemoglobin levels, and adjustments to iron metabolism result from this. Because of this mode of action, Vadadustat holds great promise as a treatment for anemia associated with chronic renal disease, a condition in which normal erythropoiesis is impaired.

What Are the Benefits of Vadadustat?

The benefits of Vadadustat include

• Stimulates Endogenous Erythropoietin Production: Vadadustat encourages the body's natural erythropoietin production by triggering the physiological response to hypoxia (inadequate oxygen). This promotes the synthesis of red blood cells and hemoglobin, which aids in managing anemia.

• Improves Oxygen transport: Vadadustat enhances oxygen transport to tissues by elevating the synthesis of red blood cells.

• Mimics Physiological Response to Hypoxia: Vadadustat is made to resemble how altitude affects oxygen availability in the body. The hypoxia-inducible factor is subsequently stabilized as a result, increasing the formation of red blood cells.

• Oral Administration: Patients may find it more convenient to receive Vadadustat orally than injectable treatments.

How Is Vadadustat Administered?

• As directed by the healthcare professional, take Vadadustat precisely as prescribed.

• Unless instructed otherwise by the healthcare practitioner, do not adjust the dosage.

• Vadadustat can be administered with or without food.

• It is recommended that Vadadustat capsules be swallowed whole. Tablets should not be chewed, cut, or smashed.

• Vadadustat is a daily medication that can be administered before, during, or after dialysis.

• Take Vadadustat for at least one hour before consuming any of the subsequent medications:

  • Supplements containing iron.

  • Iron-containing items.

  • Iron-containing phosphate binders.

• Take Vadadustat for no less than one or two hours following the ingestion of the following:

  • Phosphodiesterase binders without iron.

• When taking Vadadustat, if patients forget to take a dose, they should take it as soon as they remember the same day and then take the next dose at the scheduled time the following day. Patients should take no more than one dosage per day.

• If patients take more Vadadustat than is recommended, promptly notify the healthcare provider.

• The healthcare professional will perform specific blood tests before starting Vadadustat and as needed throughout treatment.

• Depending on the outcomes of the blood tests, the healthcare professional might adjust the amount of Vadadustat patients take.

• A 300 mg (milligrams) starting dose of Vadadustat should be taken once daily, with or without food.

• Track hemoglobin levels monthly after starting or modifying a dosage of Vadadustat.

• Raising the Vadadustat dosage should only happen once every four weeks. Doses can be lowered more often.

• Modify the Vadadustat dosage in 150 mg increments to reach or sustain 10 g/dL (grams per deciliter) to 11 g/dL hemoglobin levels. Doses might be as little as 150 mg or as much as 600 mg.

What Are the Side Effects of Vadadustat?

The most frequent side effects of Vadadustat (occurring at greater than or equal to 10 percent) were diarrhea and hypertension.

What Are the Things to Inform the Doctor Before Taking Vadadustat?

• If patients have uncontrolled high blood pressure (hypertension) or are allergic to any of the inactive substances in Vadadustat or any combination of these, avoid using Vadadustat.

• Inform the physician of all of the medical conditions before starting Vadadustat, including if patients have

  • Heart disease.

  • History of stroke or brain attack (occurs due to disruption of blood supply to the brain).

  • Liver issues.

  • High blood pressure.

  • History of seizure.

  • History of esophageal, stomach, or intestinal lining damage, such as ulcers.

  • The habit of tobacco or drinking alcohol.

  • Cancer.

Patients currently nursing, intending to start nursing, pregnant, or to get pregnant are also considered.

Dietary Considerations:

Follow the normal diet unless otherwise advised by a healthcare professional.

Missed Dose:

If a dose is missed, Vadadustat should be taken as soon as patients recall during the same day. The next day, take the next dose at the scheduled time. Never exceed one dosage in a single day.

Overdose:

Extended pharmacologic effects, such as elevated hemoglobin levels and subsequent polycythemia, can result from Vadadustat overdose. Appropriate interventions, such as dose reduction or stopping medication, should be used to manage patients.

Storage and Handling:

• Keep Vadadustat in storage between 68°F (degrees Fahrenheit) and 77°F (20°C (degrees Celsius) and 25°C) at room temperature.

• Keep Vafdadustat out of children's reach.

For Doctors

Pharmacodynamics

It was discovered that Vadadustat was used to treat anemia in adult patients with dialysis-dependent chronic renal disease, fulfilled primary hemoglobin level endpoints, and was non-inferior to Darbepoetin alfa. It was linked, nevertheless, to comparable risks of thromboembolic events, hepatic impairment, hepatotoxicity, convulsions, and elevated blood pressure, in addition to death, myocardial infarction, and stroke.

Mechanism of Action

Transcription factors known as hypoxia-inducible factors (HIFs) control several functions, including cellular viability, when there are low oxygen levels. Under normoxic circumstances, prolyl-hydroxylase dioxygenases break down HIFs. By inhibiting HIF-prolyl-hydroxylases, Vadadustat raises HIF activity in the absence of hypoxia, promoting the generation of endogenous erythropoietin and the mobilization of iron. This results in corrected iron metabolism and elevated hemoglobin levels, especially in patients with chronic renal disease who have defective normal erythropoiesis.

Pharmacokinetics

• Absorption: With a Tmax (time to peak drug concentration) of two to three hours, Vadadustat is quickly absorbed following single and repeated dosages. One can take Vadadustat with or without meals. The average Vadadustat blood-to-plasma ratio increased from 0.50 to 0.55, indicating a negligible amount of Vadadustat sequestered within red blood cells.

• Distribution: Vadadustat has a protein binding rate of 99.5 percent and a distribution volume of 392 ounces in human plasma.

• Metabolism: Vadadustat is predominantly metabolized by UGT enzymes, which use direct glucuronidation to generate O-glucuronide conjugates. It has very little metabolism through cytochrome P450s. Vadadustat-O-glucuronide, which accounts for 15 percent of plasma radioactivity AUC (area under the curve), is the main metabolite. Vadadustat acyl glucuronide makes up 0.047 percent of the total radioactivity and is a minor metabolite. Its metabolites are all inactive.

• Excretion: According to the study, 85.9 percent of the radiolabeled medication Vadadustat was recovered in healthy patients; 58.9 percent was identified in urine and 26.9 percent in feces. In individuals with dialysis-dependent chronic renal disease, its half-life was 9.2 hours. In healthy participants, its clearance varied from 1.7 to 1.9 L/h (liters per hour), but in patients with chronic renal disease, it was 0.8 L/h.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A six-month trial in transgenic mice and a two-year study in rats indicated that Vadadustat, a medication used in both animals, was not carcinogenic at doses of 2, 7, and 20 mg/kg/day (milligrams per kilogram per day) in the former and 5, 15, and 50 mg/kg/day in the latter. It did not exhibit any clastogenic activity in rats or mutagenicity in vitro. Up to 80 mg/kg/day (1.5 times the maximum recommended human dose (MRHD) based on AUC), it did not affect fertility or reproduction in rats in studies on the toxicity to early embryonic development and fertility. Vadadustat is, therefore, not regarded as genotoxic.

Drug Interactions

• Vadadustat's exposure can be decreased by co-administration with phosphate binders, iron-containing products, or iron supplements. Give Vadadustat at least an hour before using iron-containing products.

• According to the study, Vadadustat's AUC in the blood may rise if OAT (organic anion transporter)1 or OAT3 inhibitors are also taken simultaneously. Monitor the response of hemoglobin (Hb) to Vadadustat.

• Vadadustat's product labeling may indicate that it should raise the exposure to BCRP (breast cancer resistance protein) substrates and change the dosage.

• When given with other statins, such as Rosuvastatin and Simvastatin, Vadadustat increases the peak plasma concentration and AUC and adjusts the statin dosage.

• Vadadustat should be closely watched and may enhance exposure to concurrently given OAT3 substrates.

Clinical Studies

The trial assessed Vadadustat's once-daily effectiveness and safety in treating anemia in adult chronic kidney disease (CKD) patients receiving dialysis. 3923 dialysis-dependent CKD individuals with baseline hemoglobin levels between eight and 11 g/dL in the United States (US) and 9 to 12 g/dL outside the US participated in the trials. Patients with incident DD-CKD who started dialysis within 16 weeks of trial participation and were either erythropoietin stimulating agents (ESA)-naive, had little to no past ESA use, or were still on ESAs were included in INNO2VATE-1. Patients who had switched from earlier ESA therapy and had been on chronic maintenance dialysis for more than 12 weeks were included in INNO2VATE-2. The time intervals between commencing Vadadustat and starting dialysis were, respectively, 0.1 (0.01 to 0.4), 2.7 (0.2 to 31.3), and 2.3 (0.01 to 31.3) years, in the median and range. In both studies, Vadadustat and Darbepoetin alfa performed equally well at restoring and sustaining hemoglobin levels across goal ranges that were particular to a given region. Regarding age, gender, race, and area, there were no discernible variations in the responses to Vadadustat among the subgroups.

Use in Specific Populations

• Pregnancy: Vadadustat is not recommended during pregnancy as it may cause harm to the fetus.

• Breastfeeding: It is not advised to begin breastfeeding a baby until two days after the last Vadadustat dose.

• Hepatic Impairment: Patients with active, acute liver disease or cirrhosis should not take Vadadustat.

• Pediatric Use: It is unknown if Vadadustat is safe and effective for pediatric patients.

• Geriatric Use: The safety or efficacy of Vadadustat did not differ significantly between patients 65 years of age and older or between older and younger adult patients.