Dupilumab

Dupilumab belongs to the Monoclonal IgG4 Antibodies Pharmacological class.

Dupilumab is approved for the treatment of Atopic Dermatitis, Asthma, Chronic Rhinosinusitis with Nasal Polyposis, Eosinophilic Esophagitis

The volume of distribution of Dupilumab was found to be 4.8 ± 1.3 L. There is no significant hepatic metabolism data for Dupilumab. Dupilumab is mainly excreted in parallel linear and parallel non-linear pathways.

The common side effects associated with Dupilumab are toothache, gastritis, conjunctivitis, throat pain, etc.

Dupilumab is available in the form of Subcutaneous injections for adults and pediatric patients.

Dupilumab is available in India, U.K., U.S., Canada, India, E.U., China, Japan, and Australia.

Dupilumab is said to be a human monoclonal IgG4 antibody that inhibits interleukin-4 and interleukin-13 signaling by specifically binding to the IL-4Rα subunit which is shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits Interleukin-4 signaling via the Type I receptor and both Interleukin-4 and Interleukin-13 signaling through the Type II receptor. Blocking InterleukinL-4Rα with dupilumab inhibits Interleukin-4 and Interleukin-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines, and IgE.

Dupilumab hence leads to relief from Atopic Dermatitis, Asthma, Chronic Rhinosinusitis with Nasal Polyposis, Eosinophilic Esophagitis

Dupilumab onset of action is found to be 2-4 weeks, and the duration of action was found to be 16 weeks.

After the administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab Cmax was found to be 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively and the Tmax was found to be ranging from 3 to 7 days which was followed by the administration of a single subcutaneous dose ranging from 75 to 600 mg.

Dupilumab is available in Subcutaneous Injection.

The dupilumab pre-filled injection pen is not intended for use in children aged below 12 years. For children who are aged between 6 to 11 years and are suffering from atopic dermatitis, and asthma, the dupilumab pre-filled syringe is appropriate for administration.

Dupilumab is to be administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel and the upper arm can also be used.

For the initial 600 mg dose, two 300 mg injections are to be administered consecutively at different sites of injection.

Dupilumab should not be injected into damaged and tender skin. It is recommended to rotate the site of injection with each injection.

Dupilumab is used in the treatment of:

• Atopic Dermatitis
• Asthma
• Chronic Rhinosinusitis with Nasal Polyposis
• Eosinophilic Esophagitis

Dupilumab can help to relieve symptoms of Atopic Dermatitis, Asthma, Chronic Rhinosinusitis with Nasal Polyposis, Eosinophilic Esophagitis

Dupilumab is approved for use in the following clinical indications:

• Atopic Dermatitis
• Asthma
• Chronic Rhinosinusitis with Nasal Polyposis
• Eosinophilic Esophagitis

Dosage for Atopic Dermatitis

Adults

As an initial dose of 600 mg i.e.two 300 mg injections), followed by 300 mg given every other week.

Pediatric Patients who are aged 6 Months to 5 Years

5 to less than 15 kg: A dose of 200 mg i.e. one 200 mg injection for every 4 weeks

15 to less than 30 kg: A dose of 300 mg i.e.one 300 mg injection every 4 weeks

Pediatric Patients are aged 6 Years to 17 Years

15 to less than 30 kg : Initial Dose : 600 mg i.e.two 300 mg injections)

Subsequent Doses: 300 mg every 4 weeks

30 to less than 60 kg : Initial Dose : 400 mg i.e.two 200 mg injections

Subsequent Doses: 200 mg every other week

60 kg or more : Initial Dose : 600 mg i.e.two 300 mg injections

Subsequent Doses: 300 mg every other week

Dosage for Asthma

Dosage in Adult and Pediatric Patients aged 12 Years and Older

Initial Loading Dose : 400 mg i.e.two 200 mg injections or 600 mg i.e.two 300 mg injections

Subsequent Dosage: 200 mg every 2 weeks or 300 mg every 2 weeks

For patients with oral corticosteroid-dependent asthma / with co-morbid moderate-to-severe atopic dermatitis/adults with co-morbid chronic rhinosinusitis with nasal polyposis

Initial Dose : 600 mg i.e..two 300 mg injections

Subsequent Dosage: 300 mg every 2 weeks

Pediatric Patients aged 6 to 11 Years

15 to less than 30 kg: Are given 100 mg every other week / 300 mg every four weeks

more than or equal to 30 kg: 200 mg every other week

Chronic Rhinosinusitis with Nasal Polyposis

Adult patients are given 300 mg given every other week.

Dosage for Eosinophilic Esophagitis

Adult and pediatric patients aged 12 years

and older, who are weighing at least 40 kg, are given 300 mg every week

Subcutaneous:

Single-dose pre-filled syringe with needle shield as:

300 mg/2 mL , 200 mg/1.14 mL, 100 mg/0.67 mL

Single-dose pre-filled pen as:

300 mg/2 mL , 200 mg/1.14 mL

Subcutaneous pre-filled syringe

Dupilumab may be contraindicated in pediatric patients having a previous history condition of Hypersensitivity to Dupilumab or to the ingredients of the medication.

The Treating physician should closely monitor the patient and keep pharmacovigilance as follows:

• Hypersensitivity: Hypersensitivity reactions which include anaphylaxis, serum sickness, angioedema, urticaria, rash, erythema nodosum, and erythema multiforme has been reported to have occurred. It is advised to Discontinue Dipilumab in the event of a hypersensitivity reaction.

• Conjunctivitis and Keratitis: Patients are advised to report new onset or worsening eye symptoms to their healthcare provider. Consider ophthalmological examination, as appropriate.

• Eosinophilic Conditions: It is advised to be alert to vasculitic rash, worsening pulmonary symptoms, and/or neuropathy, especially upon reduction of oral corticosteroids.

• Reduction of Corticosteroid Dosage: It is not advised to discontinue systemic, topical, or inhaled corticosteroids abruptly upon initiation of Dupilumab. Decrease steroids gradually, if appropriate.

• Arthralgia: Patients are advised to report new onset or worsening joint symptoms to their healthcare provider.

• Parasitic (Helminth) Infections: Pre-existing helminth infections is treated before initiating Dupilumab. If patients get infected while receiving Dupilumab and they do not respond to anti-helminth treatment, discontinue Dupilumab until the infection resolves.

• Vaccinations: Avoid the use of live vaccines.

It is not known whether Dupilumab may be excreted in human milk hence it is advised that Dupilimab should be used only if the potential benefits outweigh the potential risks

The case reports and case series with Dupilumab use in pregnant women have not identified drug-associated risks such as major birth defects, miscarriage, etc. As the Human IgG antibodies are known to cross the placental barrier hence Dupilumab might be transmitted from the mother to the developing baby during pregnancy. No adverse developmental adverse effects were observed in newborn to pregnant monkeys after subcutaneous administration that are at doses up to 10-times the maximum recommended human dose. In the U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies was found to be 2% to 4% and 15% to 20%, respectively.

No sufficient scientific evidence was traceable regarding the use and safety of Dupilumab in concurrent use with any particular food.

The adverse reactions related to Dupilumab can be categorized as:

Common

• Excessive tearing
• Fever
• Headache
• Loss of voice
• Sneezing
• Stuffy or runny nose
• Unusual tiredness or weakness
• Body aches
• Burning or dry eyes
• Chills
• Cough
• Difficulty in breathing
• Ear congestion

Less Common

• Chest pain
• Lump or growth on the skin

Rare

• Slurred speech
• Sudden loss of coordination
• Trouble breathing
• Trouble swallowing
• Painful or difficult urination
• Scaly patches on the skin
• Skin rash
• Sore
• Throat
• Swollen glands
• Unusual bleeding or bruising
• Black stools
• Blistering, crusting, or reddening of the skin
• Vision changes
• Feeling of discomfort
• Hives, itching
• Dizziness, fainting
• Muscle aches
• Pain
• Severe, sudden headache

Live vaccines

Live Vaccines should be avoided with Dupilumab

Interactions with CYP450 Substrates

The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-4, IL-6, IL-10, IL-13, TNFα, and IFN) during chronic inflammation. Thus, Dupilumab, an antagonist of IL-4 receptor alpha, could modulate the formation of CYP450 enzymes. Therefore, upon initiation or discontinuation of Dupilumab in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index monitoring for effect e.g., for warfarin or drug concentration e.g., for cyclosporine and dosage modification of the CYP450 substrate should be considered.

The common side of Dupilumab includes the following:

• Toothache
• Joint pain
• Eyelid Inflammation
• Gastritis
• Conjunctivitis
• Throat Pain
• Pain at the site of injection
• Eosinophilia
• Oral herpes

Pregnancy

Pregnancy Category C

The case reports and case series with Dupilumab use in pregnant women have not identified drug-associated risks such as major birth defects, miscarriage etc. As the Human IgG antibodies are known to cross the placental barrier hence Dupilumab might be transmitted from the mother to the developing fetus. No adverse developmental adverse effects were observed in newborn to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis at doses up to 10-times the maximum recommended human dose. In the U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies was found to be 2% to 4% and 15% to 20%, respectively.

Nursing Mothers

It is not known whether Dupilumab is maybe excreted in milk hence it is advised that Dupilimab should be used only if the potential benefits outweigh the potential risks

Geriatric Use

Out of the 1472 subjects suffering from atopic dermatitis exposed to Dupilumab in a dose-ranging study and placebo-controlled trials, 67 subjects were aged 65 years or older. Clinical studies of Dupilumab in patients with atopic dermatitis did not include sufficient numbers of subjects who were aged 65 years and over to determine whether they respond differently from younger subjects. Out of the 1977 subjects with asthma exposed to Dupilumab, a total of 240 subjects were aged 65 years or older. Efficacy and safety in this age group were found to be similar to the overall population studied. Out of the 440 subjects with Chronic rhinosinusitis with nasal polyps exposed to Dupilumab, a total of 79 subjects were aged 65 years or older. Efficacy and safety in this age group were found to be similar to the overall population studied.

The physician should be vigilant about the knowledge and treatment pertaining to the identification and treatment of overdosage of Dupilumab.

No data from clinical studies were found or available on overdosage.

Pharmacodynamics

Dupilumab is an recombinant human IgG4 antibody to the Interleukin-4 receptor .It works by inhibiting the activation of certain pro-inflammatory cytokines that are involved in the pathophysiology of several allergic and atopic conditions, which includes asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies. In vivo, dupilumab has shown to reduce the levels of type 2 inflammatory biomarkers which are associated with disease atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed.

An open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied .

Pharmacokinetics

• Absorption

The Cmax followed by the administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab was found to be 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively. The Tmax of Dupilumab ranged from 3 to 7 days followed by the administration of a single subcutaneous dose which ranged from 75 to 600 mg.7 Following a subcutaneous dose, the absolute bioavailability of dupilumab was found between 61% and 64% in patients sufferig from atopic dermatitis / asthma.

In clinical trials, the steady-state concentrations were found to be reached by week 16 which followed the administration of 600 mg starting dose of Dupilumab and 300 mg dose every other week. At these concentrations, the mean trough concentrations for 300 mg dose ranged from 60.3 ± 35.1 mcg/mL to 79.9 ± 41.4 mcg/mL and for 200 mg dose from 29.2 ± 18.7 to 36.5 ± 22.2 mcg/mL dose administered every other week.

• Volume of distribution

The estimated volume of distribution of Dupilumab is found to be 4.8 ± 1.3 L.

• Metabolism

Dupilumab does not undergo significant hepatic metabolism. It is understood that Dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, which is as often observed with endogenous IgG.

• Route of elimination

Dupilumab does not undergo significant renal elimination , being a monoclonal antibody. At higher concentrations, dupilumab is found to be primarily cleared through a non-saturable proteolytic pathway and at lower concentrations, it is found to undergoe a non-linear saturable IL-4R α target-mediated elimination.

• https://www.healthline.com/health/drugs/Dupilumab-side-effects#side-effects-explained
• https://www.mayoclinic.org/drugs-supplements/dupilumab-subcutaneous-route/side-effects/drg-20406153?p=1
• https://reference.medscape.com/drug/Dupilumab-dupilumab-1000131#4
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761055lbl.pdf
• https://go.drugbank.com/drugs/DB12159
• https://medlineplus.gov/druginfo/meds/a617021.html
• https://www.Dupilumab.com/
• www.ema.europa.eu/en/medicines/human/EPAR/Dupilumab
• https://www.medicines.org.uk/emc/product/11321/smpc#gref