Mavorixafor - Mechanism of Action, Uses, Dosage, and Side Effects

Overview

Mavorixafor is an antagonist of the CXC chemokine receptor 4 (CXCR4). On April 29, 2024, the Food and Drug Administration (FDA) granted its initial approval for the treatment of WHIM (warts, infections, hypogammaglobulinemia, and myelokathexis) syndrome, a hereditary immunodeficiency condition marked by a decrease in mature neutrophils and lymphocytes.

Mutations in the CXCR4 gene promote the overactivation of CXCR4 signaling pathways, which is the cause of WHIM syndrome. Mavorixafor inhibits CXCR4 from being activated. Mavorixafor is being studied in the following disorders, which include B-cell non-Hodgkin lymphoma (blood cancer affects lymphocytes), Waldenstrom's macroglobulinemia (rare blood cancer comprised of excess abnormal white blood cells), melanoma (skin cancer), HIV (human immunodeficiency virus), and solid tumors. These conditions have also been linked to CXCR4 mutations.

Drug Group

Mavorixafor belongs to a drug class known as CXC chemokine receptor 4 antagonists and enhances immune cell trafficking and homeostasis by blocking the CXCR4 receptor. It is helpful in treating WHIM syndrome, a disorder marked by a decline in immune cells, as it boosts the body's capacity to fight infections by increasing the count of mature neutrophils and lymphocytes.

Indications

A CXC chemokine receptor 4 antagonist called Mavorixafor is recommended for patients aged 12 years and older who have WHIM syndrome (hypogammaglobulinemia (low immunoglobulin levels), infections, warts (painless growth), and myelokathexis (a congenital disorder that causes severe leukopenia (low leukocytes) and neutropenia (low neutrophils) to boost the count of mature neutrophils and lymphocytes in the blood.

Contraindications

It is not advised to use Mavorixafor with drugs that significantly rely on CYP2D6 or cytochrome P450 2D6 for clearance.

Dosage Forms and Available Strengths

Mavorixafor capsules have a white body and a light blue cap. They are opaque, hard gelatin capsules containing 100 mg (milligrams).

For Patients

What Is WHIM Syndrome?

Warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis are the hallmarks of WHIM syndrome, a rare congenital immunodeficiency condition. It is brought on by autosomal dominant mutations in the CXCR4 chemokine receptor gene, which truncate the receptor's carboxy terminus. Individuals who suffer from WHIM syndrome are more vulnerable to viral and bacterial infections.

How Does Mavorixafor Work?

Mavorixafor preferentially attaches to CXCR4 and inhibits the ligand, stromal cell-derived factor 1, which reduces the migration and proliferation of cells that overexpress CXCR4. Preventing immune cells from becoming stuck in the bone marrow helps lessen WHIM syndrome symptoms like infections and warts. Mavorixafor dose-dependently raises absolute neutrophil and lymphocyte counts and the mobilization and trafficking of white blood cells from the bone marrow.

What Are the Benefits of Mavorixafor?

Mavorixafor provides various advantages, especially for those who suffer from WHIM syndrome:

• Boosts White Blood Cell Counts: By boosting the mobilization and trafficking of leucocytes from the bone marrow, Mavorixafor helps to lessen the symptoms of WHIM syndrome. Both the absolute neutrophil and absolute lymphocyte counts rise in a dose-dependent manner.

• Diminishes Infection Frequency, Severity, and Duration: Research has demonstrated that Mavorixafor helps people with WHIM syndrome experience fewer, milder infections with shorter durations.

• Well-tolerated: Mavorixafor has demonstrated good tolerability in clinical trials.

• Orally Available: Patients may find Mavorixafor more convenient than an oral medication.

How Is Mavorixafor Administered?

Typically, Mavorixafor is used once a day before breakfast. After an overnight fast, take one dose on an empty stomach, wait at least half an hour before eating, and swallow whole, not chewing, opening, or breaking.

The typical Mavorixafor dosage is determined by weight:

• Over 110 Pounds: 400 mg once a day orally.

• Less or Equal to 110 Pounds: 300 mg once a day orally.

What Are the Side Effects of Mavorixafor?

While extraordinarily severe and perhaps fatal adverse effects are rare, some people may experience them when taking Mavorixafor. Inform the physician if patients experience any of the following warning signs or symptoms, which could indicate serious side effects, and get medical attention right away:

• An allergic reaction may manifest as a rash, hives, itching, red, swollen, blistered, or peeling skin, wheezing, tightness in the chest or throat, difficulty swallowing, breathing, or speaking, or unexpected hoarseness, as well as facial, tongue, throat, or mouth swelling.

• Any bleeding or bruises that go undiagnosed.

• A circular spot of skin that can be grey, brown, black, pink, or tan. There may potentially be other spots.

• This medication may cause a prolonged QT interval, and an irregular heartbeat. If patients experience a fast heartbeat, an irregular pulse, or faintness, contact the doctor immediately.

The following were the most frequent side effects that affected at least 10 percent of patients using Mavorixafor:

• Thrombocytopenia (low platelet counts).

• A skin rash, like pityriasis (a rapidly evolving skin rash).

• Sneezing, stuffiness, and congestion in the nose.

• Nosebleeds.

• Vomiting.

• Dizziness.

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

1. Inform the doctor before using Mavorixafor if patients have:

• An allergy to any component of Mavorexifor or any other medication, food, or substance.

• Health issues related to liver illness or kidney disease.

• Other electrolyte issues or low potassium levels.

• Take any medications (prescription or over-the-counter, vitamins, natural products) that should not be taken in conjunction with this medication, such as certain medications for HIV, infections, or seizures (uncontrolled electrical activity in the brain). This medication should not be taken with several other medications.

• Use any product containing St. John's wort or goldenseal.

• A history of cardiac problems, such as a QTc prolongation or an arrhythmia (irregular heartbeat).

• Low platelet counts.

• Skin ailments.

• Bleed from the nose frequently.

2. If patients are nursing, are pregnant, may become pregnant, or want to get pregnant.

3. If patients are taking different prescription drugs.

Dietary Considerations

Grapefruit is a potent CYP3A4 inhibitor, so it should not be consumed with Mavorixafor, which may raise the possibility of adverse effects.

Missed Dose

• Return to the regular schedule and skip the missed Mavorixafor dose.

• Take only one dose of Mavorixafor on the same day.

Storage and Handling

Keep Mavorixafor in the refrigerator between 2°C (degrees Celsius) and 8°C (36°F (degrees Fahrenheit) and 46°F). Keep the bottle shut tightly. Store it in its original container and use it as directed to keep it dry.

Disposal

Remove any unused or expired Mavorixafor medications. Unless instructed otherwise, never pour down the drain or flush down the toilet. For advice on properly disposing of Mavorixafor, speak to a pharmacist. In the locality, there might be the FDA's drug take-back programs.

For Doctors

What Are the Pharmacological Actions of Mavorixafor?

Pharmacodynamics

Mavorixafor increases bone marrow-derived white blood cell mobilization and trafficking, which helps to lessen WHIM syndrome symptoms like infections and warts. Mavorixafor raises the absolute neutrophil and lymphocyte counts in a dose-dependent manner. Mavorixafor was demonstrated to lengthen the QT interval in healthy individuals in a concentration-dependent way.

Mechanism of Action

Mavorixafor is an orally bioavailable antagonist of CXC Chemokine Receptor 4 (CXCR4) that prevents stromal-derived factor-1 alpha (SDF-1 alpha) or CXC Chemokine Ligand 12 (CXCL12) from binding to the CXCR4 ligand. SDF-1 or CXCR4 mediates leukocyte trafficking and homing to and from the bone marrow compartment.

Patients with WHIM syndrome have gain-of-function mutations in the CXCR4 receptor gene, which increase their sensitivity to CXCL12 and cause their bone marrow to retain more leukocytes.

Mavorixafor can block the response of both wild-type and mutant CXCR4 variants linked to WHIM syndrome to CXCL12. The outcome of Mavorixafor treatment is increased bone marrow-derived neutrophil and lymphocyte mobilization into the peripheral circulation.

Pharmacokinetics

• Absorption: When 400 mg is taken once daily, the individuals with WHIM syndrome had a mean (CV (coefficient of variance) percent) Cmax (maximum concentration) at a steady-state of 3304 (58.6 percent) ng/mL (nanogram per milliliter) and an AUC (area under the curve) of 13970 (58.4 percent) ngxh/mL (nanograms per hour per milliliter) after 24 hours.

Mavorixafor has non-linear pharmacokinetics comprising a dose range of 50 mg (0.125 times the recommended dosage) to 400 mg, with more than dose-proportional increases in Cmax and AUC0-24h (hour). In healthy patients, Mavorixafor steady-state is attained at the highest approved recommended dosage after about nine to 12 days. The maximum authorized recommended dosage of Mavorixafor has a Tmax (time to peak drug concentration) of 2.8 hours (1.9 to 4 hours) on the median (range). Food lowers AUC and Cmax.

• Distribution: The Mavorixafor volume of distribution in adult WHIM syndrome patients was 25969 ounces. Mavorixafor is more than 93 percent bound to human plasma proteins in vitro.

• Metabolism: CYP3A4 and, to some extent, CYP2D6 are involved in the metabolism of Mavorixafor.

• Elimination: According to the study, 74.2 percent of the oral dose of radiolabeled Mavorixafor was recovered following a single dose; 61 percent of the dose was identified in feces and 13.2 percent in urine. The mean apparent clearance in healthy subjects was 62 L/h (liters per hour), and the mean terminal half-life was 82 hours. Although Mavorixafor shows partial nonlinear apparent clearance, this is not clinically significant at the suggested dosage.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility: No research exists on Mavorixafor's carcinogenicity. The in vitro bacterial reverse mutation assay (Ames test), in vitro human cell culture chromosome aberration assay, and in vivo rat bone marrow micronucleus assay did not demonstrate genotoxicity for Mavorixafor. Mavorixafor has not been used in any fertility research. Dog testes showed significant tubular shrinkage or degeneration following clinical exposure.

What Are the Drug Interactions of Mavorixafor?

• CYP2D6 Enzymes: Mavorixafor should not be taken with drugs like Fluoxetine or Amitriptyline, which heavily rely on CYP2D6 enzymes for clearance. QTc interval prolongation may result from it.

• CYP3A4 Interactions: Avoid taking potent CYP3A4 inducers along with Mavorixafor. Lower the daily dose of Mavorixafor when taken with potent CYP3A4 inhibitors. When taking moderate CYP3A4 inhibitors or P-gp inhibitors concurrently, keep a closer eye out for any negative responses linked to increased exposure to Mavorixafor. If required, lower the daily dosage of Mavorixafor.

Warnings and Precautions

• Embryo-fetal toxicity: Mavorixafor is likely to be harmful to fetuses. Encourage women who can conceive to utilize safe contraceptives.

• QTc Interval Prolongation: Mavorixafor may lengthen the QTc interval concentration-dependently when taken with other drugs or medicinal products. Adjust risk factors, evaluate QTc, monitor the course of treatment, and consider decreasing or discontinuing the dosage.

Clinical Studies

The effectiveness of Mavorixafor was assessed in patients with WHIM syndrome who were 12 years of age or older. A 52-week randomized, double-blind, placebo-controlled subset of study 1 was examined. Thirty-one patients were randomly assigned to receive Mavorixafor once daily or a placebo during the study. Improvements in absolute neutrophil counts (ANC), improvements in absolute lymphocyte counts (ALC), and a decrease in infections were used to evaluate the effectiveness of Mavorixafor.

The mean time above the ANC threshold (TATANC) was measured four times during the study. The findings indicated that Mavorixafor patients had a statistically significant longer time above the ANC threshold (TATANC) than placebo (2.8 hours). Regarding ALC, there was a statistically significant difference in the mean time above the ALC threshold (TATALC) between Mavorixafor patients and placebo (4.6 hours).

Using the Win-Ratio approach, the effectiveness of Mavorixafor was evaluated using a composite endpoint comprising the total infection and wart change scores. According to the results, patients treated with Mavorixafor had a 40 percent lower overall infection score than patients treated with a placebo, weighed by the severity of the infection. Patients treated with Mavorixafor had an approximate 60 percent reduction in the annualized infection rate. Over 52 weeks, there was no difference in the overall wart change scores between the Mavorixafor and placebo treatment arms.

Use in Specific Populations

• Pregnancy: Mavorixafor may result in improper placental development and damage to the fetus. Pregnant women should not take it, and those who could get pregnant should use reliable contraception during and for three weeks following the last dosage. If pregnant, let the doctor know right away.

• Breastfeeding: Inform women that it is not advised for them to breastfeed while taking Mavorixafor or for three weeks following the last dosage.

• Pediatric Use: The safety and efficacy of Mavorixafor in children under 12 have not been proven.

• Geriatric Use: Studies on Mavorixafor in patients with WHIM syndrome revealed that no patient was 75 years of age or older, and only five percent of patients were 65 years of age or older, suggesting that there was inadequate data to assess their response.

• Renal Impairment: Mavorixafor is not advised for individuals with end-stage renal disease or severe renal impairment.

• Hepatic Impairment: It is not advised to use Mavorixafor in individuals with moderate to severe liver impairment.