Brentuximab Vedotin is available under the brand name Adcetris. It is a special kind of drug made of a combination of drug and antibody conjugate, called ADC or antibody-drug conjugate.

It primarily targets cells that have CD-30 receptors. Brentuximab Vedotin binds to CD-30 positive cells and is allowed entry into the cells. In response to the ADC entry into the cells, MMAE (monomethyl auristatin E), a molecule is released by the cells which stops the cell cycle by disrupting the microtubular array of the cells.

What is Brentuximab Vedotin used for?

Brentuximab Vedotin is used to treat the following cancers:

• Hodgkin Lymphoma:

It is used to treat patients with Hodgkin's lymphoma who have failed two first-line multi-drug chemotherapeutic regimens or relapsed after Autologous stem cell transplantation.

• Systemic Anaplastic Large Cell Lymphoma:

It is used to treat people with systemic anaplastic large cell lymphoma who have failed at least one first-line multidrug chemotherapy regimen or experienced recurrence.

Brentuximab Vedotin Dosing:

The usual dose in patients with normal kidney and liver functions is: [Ref]

• Every three weeks, an intravenous infusion of 1.8 mg/kg is given over 30 minutes. The maximum dosage per session is 180 mg.
• In patients with mild to moderate kidney disease, the same dose can be used (no dosage adjustment is recommended).
• In individuals with severe renal disease, such as those who have a CrCl of 30 ml/min or fewer, it should be avoided.

Similar to this, the dosage is decreased in patients with moderate hepatic impairment (Child Class A) to 1.2 mg/kg, with a daily maximum of 120 mg.

In individuals with moderate to severe hepatic impairment, it is advised to avoid this medication (Child Class B and C).

Other conditions where the dose may need to be modified:

To avoid certain side effects associated with Adcetris, the dose may need to be modified. These conditions include:

Peripheral Neuropathy:

In patients who have severe signs and symptoms of peripheral neuropathy (Grade 4), the drug should not be used. In Grade 2 and 3 peripheral neuropathy, the drug is withheld for some time so as the signs and symptoms of neuropathy improve to at least grade 1.  

The medication is then continued at a reduced dose of 1.2 mg/kg after the symptoms become better. A lower dose of 1.2 mg/kg should be used in patients with newly developing neuropathy symptoms or grade 1 neuropathy who already have it.

Neutropenia:

Neutropenia is an expected side effect of Brentuximab Vedotin (Adcetris). Neutropenia is graded as:

• Grade 0: Neutrophils exceeding 2000/ul
• Grade 1: Neutrophils in the range of 1500 - 2000/ul
• Grade 2: Neutrophils in the range of 1000 - 1500/ul
• Grade 3: Neutrophils in the range of 500 - 1000/ul
• Grade 4: Neutrophils less than 500/ul

In patients with Grade 3 or 4 neutropenia, the dose is withheld until the neutrophil counts improve to at least 1000/ul (Grade 2) or more. In the following chemotherapy cycles, G-CSF (colony-stimulating factors) may be administered to patients with neutropenia of Grade 3 or 4.

The dose may be reduced to 1.2 mg/kg in those individuals who have persistent Grade 3 or 4 neutropenia despite G-CSF administration.

How to infuse Brentuximab Vedotin?

The dose of Adcetris is calculated based on the patient's weight. The number of 50 mg vials are taken. The water provided for reconstitution is used to prepare the solution. A 10.5 ml of sterile water is mixed with the powder in the vial.

Instead of spraying the powder directly, the sterile water must be aimed at the vial's wall. Swirl the solution in your palm once it has been made, but don't shake it.

Immediately dilute it by adding it to the infusion bag. It can be stored at 2 - 8 C before dilution. Do not freeze it. The solution can be mixed with 100 ml of 0.9% saline, dextrose water, or ringer lactate. The concentration of the final solution may range from 0.4 mg per ml-1.8 mg per ml.

Side effects?

Before discussing the side effects of Brentuximab Vedotin, it is important not to administer it with concomitant Bleomycin because of the increased risk of pulmonary fibrosis.

In addition, the following side effects need special attention when administering Brentuximab Vedotin:

Peripheral neuropathy:

A fairly frequent adverse effect of the medication Brentuximab Vedotin is peripheral neuropathy. It has been observed in more than half of the patients who received Brentuximab Vedotin (Adcetris). Most patients develop sensory neuropathy and improve after the treatment is discontinued or the dose is reduced.

All patients should be monitored for symptoms and signs of peripheral neuropathy, especially sensory neuropathy. Symptoms of sensory neuropathy include numbness, tingling, paraesthesias, and burning sensation.

Allergic reactions:

Patients are at risk of developing allergic reactions. These reactions may be mild and manifest as itching and rash or severe enough to require intensive monitoring and intravenous pressors.

Patients should be monitored during the infusion. All patients must be premedicated before the infusion with acetaminophen, antihistamine, and corticosteroid injection.

Blood-related toxicity:

Bone marrow suppression is an expected side effect of Brentuximab Vedotin (Adcetris). Mild leukopenia and thrombocytopenia may not need treatment interruption. However, in patients with Grade III or IV neutropenia, treatment interruption, dose reduction, and the administration of G_CSF (Filgrastim or PEG-Filgrastim) may be required.

Opportunistic Infections:

Serious bacterial and fungal infections may result in pneumonia, sepsis, and septic shock. Patients must avoid getting in close contact with a person who is sick and maintain clean hygiene.

Early treatment of any opportunistic infection is important.

Tumor Lysis Syndrome:

Cell lysis can result in tumor lysis syndrome, especially in patients who have a high tumor burden. Patients may develop hyperkalemia, hypocalcemia, and hyperuricemia.

Adequate hydration, management of hyperkalemia, and prophylactic administration of allopurinol, rasburicase, or febuxostat are mandatory to avoid tumor lysis syndrome.

Liver and Nephrotoxicity:

Increased incidence of Grade 3 or higher side effects has been observed in patients with liver impairment or kidney injury. In addition, direct hepatocellular damage has also been reported in patients receiving Brentuximab Vedotin (Adcetris).

Progressive Multifocal Leukoencephalopathy:

Patients who are getting treatment for Hodgkin's lymphoma or other hematological malignancies are immunocompromised and at risk of infections. JC virus infections can occur in these infections. 

JC virus infection can cause progressive multifocal leukoencephalopathy that may result in the death of the patient. When PML is suspected, the treatment should be discontinued.

Skin-related serious side effects:

Steven-Johnson syndrome is a serious side effect of the drug. Patients who develop any skin rash that is progressive or involves the mucosa of the oral cavity or the eyes should not receive the treatment any further. 

All patients should be treated with hydrocortisone, antibiotics, and fluid resuscitation.

Embryo and fetal toxicity:

Brentuximab Vedotin (Adcetris) has been observed in animal studies to cause serious fetal toxicity including the death of the fetus. It should not be given to pregnant women or women intending to become pregnant.

Other side effects of Brentuximab Vedotin (Adcetris): 

Other side effects of Adcetris include:

Neurological side effects:

• Headache
• Dizziness
• Motor neuropathy

Blood-related side effects:

• Neutropenia
• Anemia
• Thrombocytopenia
• Lymphadenopathy

General systemic disorders:

• Fatigue
• Lethargy
• Edema
• Pain
• Chills
• Reduced appetite
• Weight loss

Infections:

• Upper respiratory infection

Gastrointestinal side effects:

• Diarrhea
• Vomiting
• Abdominal pain
• Constipation

Skin-related side effects:

• Rash
• Itching
• Alopecia
• Dry Skin

Chest-related side effects:

• Cough
• Dyspnea
• Oropharyngeal pain

Skeletal side effects:

• Pain
• Myalgias
• Back pain
• Limbs pain

Psychiatric disorders

• Insomnia
• anxiety

Brentuximab Vedotin (Adcetris) Drug Interactions:

MMAE is released when the drug-antibody conjugate is internalized. MMAE is metabolized by CYP3A.

Ketoconazole and other CYP3A inhibitors: Ketoconazole is a strong CYP3A inhibitor. It increases Adcetris levels in the blood by 34%.

Rifampicin and other CYP3A inducers: Rifampicin is an inducer of CYP3A. It reduces the blood levels of the drug when co-administered.

P-gp inhibitors: Co-administration of Adcetris with P-gp inhibitors can increase the levels of the drug in the blood.

Brentuximab Vedotin (Adcetris) MOA and Pharmacology:

Brentuximab Vedotin (Adcetris) is an ADC (antibody-drug conjugate. It is a chimeric IgG that targets cells expressing CD 30.

After the drug binds the CD 30 positive cells, it is internalized. This results in the release of MMAE which disrupts the microtubular structures of the cells resulting in cell cycle interruption and death.

QTc prolonging effect: It exhibits a mild QTc prolonging effect.

Half-life elimination: It has a terminal half-life elimination of about 4 - 6 hours.

Brentuximab Vedotin (Adcetris) price in Pakistan:

It is not available in Pakistan. For needy patients, application to DRAP is written and the drug may be acquired from nearby countries on a compassionate basis.