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

Overview

Deuruxolitinib, an oral medication for treating severe alopecia areata, is an oral selective inhibitor of Janus kinase (JAK) inhibitors. Deuruxolitinib was approved by the United States Food and Drug Administration (US FDA) for severe alopecia areata (an autoimmune disease that affects hair follicles, nails, and retinal pigment epithelium) on July 26, 2024. It is the third FDA-approved treatment for this condition. Clinical trial data has shown that Deuruxolitinib is effective and safe for hair regrowth in adults with alopecia areata, with successful tolerability in moderate to severe cases.

Drug Group

Deuruxolitinib is a Janus kinase (JAK) inhibitor that specifically modulates JAK1 and JAK2 to ensure immune and inflammation signaling pathways. It has proven effective in encouraging hair regrowth in adults with severe types of alopecia areata.

Indications

Deuruxolitinib is used to manage moderate to severe alopecia areata in adults only.

Limitations of Use:

Deuruxolitinib is contraindicated with other JAK inhibitors, potent immunosuppressants, Cyclosporine, or biologic immunomodulators.

Contraindications

Deuruxolitinib should not be administered in patients with a poor CYP2C9 (cytochrome P450 family 2 subfamily C member 9) metabolizer genotype or moderate or strong CYP2C9 inhibitors.

Dosage Forms and Available Strengths

Deuruxolitinib is formulated in a tablet with a normal registered dosage of eight milligrams (mg).

Warnings and Precautions

• Increased Risk of Deuruxolitinib-Associated Serious Adverse Reactions in CYP2C9 Poor Metabolizers or with Concomitant Use of Moderate or Strong CYP2C9 Inhibitors: Deuruxolitinib is contraindicated in patients with CYP2C9 poor metabolism and patients receiving a moderate or strong CYP2C9 inhibitor.

• Gastrointestinal Perforations: Pay close attention to patients at higher risk of developing gastrointestinal perforation. Evaluate promptly patients presenting with new-onset abdominal symptoms.

• Lipid Elevations, Anemia, Neutropenia, and Lymphopenia: Constant observation for alteration in lipid profile, hemoglobin, neutrophil, and lymphocyte count.

• Immunizations: Live vaccines should not be used during Deuruxolitinib treatment or within one month before starting it.

For Patients

How Does Deuruxolitinib Work for Alopecia Areata?

Deuruxolitinib targets JAKs, specifically JAK1 and JAK2. It operates through the interference of the JAK pathway, which is essential in immune reactions and inflammation. In alopecia areata, an autoimmune disorder in which the body’s immunity attacks hair cells, Deuruxolitinib prevents this occurrence. Thus the drug holds back the immune system and facilitates hair growth even in extreme conditions.

How Is Deuruxolitinib Administered?

1. It is recommended to do the following evaluations and immunizations before and during treatment:

Before starting Deuruxolitinib therapy, do the following:

• Potential Deuruxolitinib-related interactions involve using several tests to identify the CYP2C9 genotype before treatment, including testing for CYP2C9 variants. Deuruxolitinib should not be taken by those who are CYP2C9-poor metabolizers.

• Moderate or strong CYP2C9 inhibitors are contraindicated in patients taking Deuruxolitinib. Patients with active TB (tuberculosis) should not receive Deuruxolitinib treatment, and preventive therapy should be initiated in high-risk TB patients.

• Hepatitis B or C (liver inflammation) active infection should not undergo viral hepatitis screening. Hepatitis B infection screening should adhere to medical practice protocols or consult a hepatologist.

• Contraindications of Deuruxolitinib treatment should include patients with a Lymphocyte count below 500 cells per mm3 (cubic millimeter), a neutrophil count below 1,000 cells per mm3, or a hemoglobin level below 8 g/dl (grams per deciliter). The complete blood counts must be checked during treatment, and the dosage must be adjusted based on the results.

• Patients must also update their immunizations and complete suggested vaccinations, such as herpes zoster (viral infection) immunizations, based on the guidelines recommendations.

1. The recommended dosage of Deuruxolitinb is eight milligrams twice daily.

What Are the Side Effects of Deuruxolitinib?

The most common side effects (greater than or equal to one percent) are:

• Headache.

• Acne.

• Nasopharyngitis (common cold).

• High blood creatine phosphokinase.

• Hyperlipidemia (high cholesterol).

• Fatigue.

• Weight gain.

• Lymphopenia (low lymphocyte level in blood).

• Thrombocytosis (high platelet level in blood).

• Anemia (low red blood cells).

• Skin and soft tissue infections.

• Neutropenia (low neutrophil count).

• Herpes (viral infection).

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

Inform a healthcare provider about all health conditions and other prescription or OTC medicines, vitamins, minerals, herbs, and supplements.

1. Vaccines: Patients should not get any ‘live’ vaccines while in treatment with Deuruxolitinib or within 14 days before using Deuruxolitinib. Inform the doctor if patients are currently, or have recently, been vaccinated with a live vaccine or if they plan to get a live vaccine shortly.

2. Pre-existing and Comorbidities: In case patients have any of the following, advise them to report to the healthcare provider.

• Are you currently receiving treatment for an infection or have signs of an infection, such as fever, chills, cough, etc.

• Get sick with bacteria or viruses that cannot be easily treated or repeatedly get the same sickness.

• Cancer.

• Diabetes (high blood sugar).

• Asthma (a chronic lung disease that inflames and narrows the lung airways) and chronic obstructive lung disease (COPD) (a lung disease that affects the airflow in and out of the lungs).

• Shingles.

• Tuberculosis (TB), have tested positive for TB, have had skin test conclusion positive, or have been in touch with any individual with tuberculosis.

• Human immunodeficiency virus (HIV).

• Living in areas with high environmental fungal infection or mold levels, such as Ohio, Mississippi River Valley, or the Southwestern United States.

• Poor immunity.

• Hepatitis B or C.

• Smoke or previous smoker.

• Heart attack or any other heart-related complications or stroke.

• Clots in veins of groins and thighs, lungs, and brain.

• Kidney or liver problems.

• Stomach pain, symptoms of appendicitis, diverticulitis, ulcers, stomach or intestines inflammation.

• Anemia.

1. Pregnancy: The effects of Deuruxolitinib on pregnancy are still unknown, and thus it should not be taken by pregnant and childbearing women or those who intend to get pregnant while using Deuruxolitinib. It is strongly recommended that females who may become pregnant should use contraceptives when taking Deuruxolitinib, and suitable contraceptive measures should be discussed with the doctor.

2. Breastfeeding: Do not breastfeed within one day of taking Deuruxolitinib; its effect on breast milk is unclear. Tell the doctor if the patients are breastfeeding or intend to breastfeed.

Dietary Considerations:

None.

Missed Dose:

If a dose is missed, it should not be compensated, and the patient should return to the normal schedule.

Overdose:

In case of overdosing on Deuruxolitinib, contact a medical facility, dial an emergency response center, or call a poison control center.

Storage and Handling:

Store at 20°C (degrees Celsius) to 25°C or 68°F (degrees Fahrenheit) to 77°F. It may also be stored in the temperature range of 15° to 30°C (59°F to 86°F). Keep it in the original bottle to extend the shelf life, as moisture should be stirred away from it.

For Doctors

Pharmacodynamics

In the in vitro kinase activity assay, Deuruxolitinib has shown a higher affinity to inhibit JAK (Janus kinase) 1, JAK2, and TYK (tyrosine kinase) 2 than JAK3. It also prevented whole blood IL-6 (interleukin-6) stimulated pSTAT3 (signal transducer and activator of transcription 3) in healthy subjects two hours postdose, whereas its effect in patients is elusive.

Mechanism of Action

The JAK-STAT signaling pathway, which involves four kinases of the JAK family, is involved in signaling by cytokine receptors and controls the genes for mediators of hematopoiesis and immune response. The JAK activating pathway is characterized by STATs binding to cytokine receptors and activating STATs, after which they translocate to the nucleus to participate in the regulation of gene expression.

Inflammatory disease states such as alopecia areata have been noted to exhibit dysregulated JAK activity that affects immune response. Signaling through JAK induces autoantigen expression and an autoimmune response against hair follicles by high IFN-γ and CD8+NKG2D+T cells. Deuruxolitinib is another JAK inhibitor that should help minimize the inflammation of hair follicles by acting on JAK1 and JAK2 enzymes only.

Pharmacokinetics

• Absorption: Cmax (maximum plasm concentration) and AUC (area under the curve) of Deuruxolitinib in healthy subjects increase proportionally when administered orally, which attains steady-state plasma concentrations within one to two days of twice daily dosing. Its bioavailability is 90 percent, and peak plasma concentrations are achieved within 1.5 hours. Pharmacokinetic studies showed no variations in the overall pharmacokinetic profiles observed when a high-fat, high-calorie meal was provided.

• Distribution: After the drug is introduced, the distribution volume will reach its steady state at around 50 L (liters). The concentration of Deuruxolitinib in plasma is bound by plasma protein to the extent of 91.5 percent, and the blood-to-plasma concentration ratio of Deuruxolitinib is approximately 1.3.

• Metabolism: Deuruxolitinib is mainly metabolized by CYP2C9 (76 percent) and CYP3A4 (21 percent), while CYP1A2 comprises only three percent of the total metabolism. C-21714 and C-21717 represent the two most abundant human metabolites; each has an AUC of approximately five percent of the total drug-related AUC; both are approximately 10-fold less pharmacologically active than Deuruxolitinib. The metabolic process of Deuruxolitinib and the chemical structures of its metabolites remain to be elucidated.

• Excretion: When a single dose of radiolabeled Deuruxolitinib was administered in the study, no amounts of the unchanged Deuruxolitinib dose were found in urine and feces.The mean elimination half-life is about four hours.

Toxicity

No carcinogenic potential was identified in the rasH2 transgenic mouse oral study and a 2-year rat oral carcinogenicity study with Deuruxolitinib. However, no drug-related tumors were seen in the groups of rats receiving Deuruxolitinib up to 30 mg/kg/day (milligrams per kilogram per day) by oral gavage. It was positive in an in vitro micronucleus assay. The bacterial mutation assay, Deuruxolitinib was negative in chromosome aberration and negative in the in vivo rat micronucleus. In a fertility and early embryonic development study conducted in rats, Deuruxolitinib was given to male and female rats at doses before mating, during mating or post-mating, and of the sperm from conception to gestation day 7. No toxic effects were reported at oral doses up to 100 mg/kg/day. However, effects on early embryonic development revealed reduced viable embryos, increased pre-implantation loss at doses of 30 and more mg/kg/day, and post-implantation loss and resorption at 100 mg/kg/day doses. No adverse effects on early embryonic development were observed at 10 mg/kg/day.

Drug Interactions

Strong CYP3A and moderate or strong CYP2C9 inducers: Deuruxolitinib should be avoided in conjunction with strong CYP3A modifiers and moderate or strong CYP2C9 inducers, as Deuruxolitinib metabolized by CYP2C9 and CYP3A, which may lower its effectiveness.

Moderate or strong CYP2C9 inhibitors: A precaution of Deuruxolitinib is that it should not be administered in patients receiving moderate or strong CYP2C9 inhibitors since co-administration with these agents will raise Deuruxolitinib exposure and the ensuing risk of serious adverse reactions, such as thrombosis.

Clinical Studies

Two phase 3 clinical trials involving 1209 adults who have alopecia areata and had experienced 50 percent hair loss on the scalp for six months and above. The subjects were administered eight milligrams of Deuruxolitinib orally twice daily, 12 mg of Deuruxolitinib orally twice daily, or placebo twice daily for 24 weeks. The integrated mean baseline SALT scores for all the treatment groups ranged from 85.9 to 88.6, with the mean duration of the current episode of hair loss varying from 3.7 to 3.9 years.

Eyebrow hair involvement was observed in 73 percent of the subjects, and eyelash hair involvement in 70 percent. The major outcome measure with both trials compared the percentage of subjects in each group with a SALT score of less than or equal to 20 at Week 24. Secondary measures comprised the proportion of responders on the Satisfaction of Hair Patient-Reported Outcome (SPRO) and subjects with an absolute SALT score of less than or equal to 20 at Weeks 20, 16, 12, and 8. The scalp hair loss was assessed by using the SALT score. At Week 24, the percentage of patients assigned to the treatment group was higher. The toxicity response was defined as SALT less than or equal to 20 (80 percent or more scalp hair) and SALT less than or equal to 10 (90 percent or a statistically significant increase in total scalp hair count) with Deuruxolitinib eight milligrams twice daily compared with placebo.

Use in Specific Populations

• Pregnancy: Deuruxolitinib may also have the possibility to produce adverse effects on the fetus during pregnancy, given animal studies. There is inadequate data from clinical trials to assess the QTc prolongation associated risk with major congenital malformations, miscarriage, and adverse maternal or fetal outcomes in pregnant females. Any woman capable of getting pregnant should talk to her doctor before taking the medicine and should never be sexually active without a correct birth control method.

• Breastfeeding: Speak with the doctor about whether one is to breastfeed or is breastfeeding during Deuruxolitinib treatment because the medication can lead to a passage through breast milk. Consult the healthcare provider about the best feeding methods to adopt when pregnant.

• Pediatric Use: The safety and efficacy of Deuruxolitinib have not been determined in children.

• Geriatric Use: The doses and clinical trials of Deuruxolitinib failed to compare the responses of the elderly subjects with those of the young population.

• Renal impairment: Deuruxolitinib has not been recommended for patients with severe renal failure or chronic kidney disease, and mild or moderate renal dysfunction does not need dose adjustment of the drug.

• Hepatic Impairment: Patients with severe hepatic impairment must not take Deuruxolitinib, while the dosage adjustments for mild or moderate hepatic impairment are unknown, and the pharmacokinetics of Deuruxolitinib are not greatly affected.

• CYP2C9 Poor Metabolizers: Deuruxolitinib adverse reactions may be heightened in CYP2C9 poor patients receiving Deuruxolitinib; however, genotype testing for CYP2C9 is lacking as FDA-cleared tests have not been established.