Adcetris (Brentuximab Vedotin): Uses, Dose, MOA, and Side effects

Brentuximab Vedotin is a breakthrough cancer treatment. It is a drug-antibody conjugate approved by the US Food and Drug Administration (FDA) for the treatment of certain types of lymphoma.

A drug-antibody conjugate is a formulation where the antibody takes the drug to specific sites, CD-30 positive cancer cells in the case of Brentuximab Vedotin, the drug is released there and acts at the specific target site.

Brentuximab vedotin is a targeted therapy that works by attaching to cancer cells and delivering a toxic substance directly to the tumor, which helps to destroy the cancer cells.

This article will provide an overview of Brentuximab Vedotin, including its mechanism of action, indications, administration and dosage, safety and side effects, clinical studies and efficacy, and future developments.

By understanding the potential of this new cancer treatment, patients and healthcare professionals can make informed decisions about the best course of treatment for their individual needs.

FDA approval of Brentuximab Vedotin

Brentuximab Vedotin was initially approved for treating Hodgkin lymphoma and anaplastic large-cell lymphoma. Later its indications were extended to include peripheral T-cell lymphoma and primary cutaneous anaplastic large-cell lymphoma.

Definition and explanation of Brentuximab Vedotin

Brentuximab Vedotin is a newer type of cancer treatment known as an antibody-drug conjugate. It is made up of two parts: a monoclonal antibody and a chemotherapy drug.

The monoclonal antibody, called Brentuximab, targets a specific protein on the surface of cancer cells called CD30. Once the antibody binds to CD30, the chemotherapy drug, called vedotin, is released directly into the cancer cell, causing it to die.

How Does Brentuximab Vedotin Work?

Brentuximab Vedotin works by targeting and binding to CD30, which is overexpressed over certain types of lymphoma cells.

Once the antibody has attached to the cancer cell, the chemotherapy drug is released into the cell, where it disrupts the microtubule network and causes the cell to die.

This targeted approach minimizes the damage to healthy cells and reduces the risk of side effects associated with traditional chemotherapy.

Adcetris (Brentuximab Vedotin) in the treatment of different types of lymphoma are:

  • Hodgkin lymphoma:

Brentuximab Vedotin (Adcetris) is approved for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation (ASCT) or at least two previous systemic therapies.

  • Anaplastic large cell lymphoma:

Adcetris is approved for the treatment of systemic anaplastic large cell lymphoma that is ALK-positive or ALK-negative and has relapsed or progressed after at least one prior systemic therapy.

  • Peripheral T-cell lymphoma:

It is also approved for the treatment of relapsed or refractory systemic anaplastic large cell lymphoma that is ALK-negative or other types of peripheral T-cell lymphoma that have relapsed or progressed after at least one prior systemic therapy.

Stage of lymphoma treated by Brentuximab Vedotin:

  • Brentuximab Vedotin may be used as a first-line treatment in certain cancers but it is generally indicated for the treatment of advanced-stage lymphoma that has relapsed or is refractory to other treatments. 

Administration and Dosage of Adcetris (Brentuximab Vedotin)

For the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma:

  • The recommended dose is 1.8 mg/kg administered every three weeks.

For the treatment of peripheral T-cell lymphoma:

  • The recommended dosage is 1.8 mg/kg administered every three weeks for up to 16 cycles.

Dosage Recommendations

Administer ADCETRIS intravenously over a half-an-hour every 3 weeks until disease progression or unacceptable toxicity.

Recommended ADCETRIS Dosage:

Patient Group    

Recommended Starting Dosage

Normal renal and hepatic function

1.8 mg/kg up to 180 mg

Renal impairment:

Mild

1.8 mg/kg up to 180 mg

Moderate

1.8 mg/kg up to 180 mg

Severe

Avoid use

Hepatic impairment:

Mild (Child-Pugh A)  

1.2 mg/kg up to 120 mg

Moderate (Child-Pugh B)

Avoid use

Severe (Child-Pugh C)     

Avoid use

Condition

Action

Peripheral Neuropathy

For new or worsening Grade 2 or 3 neuropathy, withhold the dose until recovery to Grade 1 or baseline. May restart at 1.2 mg/kg.

Discontinue treatment in Grade 4 peripheral neuropathy.

Neutropenia

Withhold the dose for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower.

Consider G-CSF prophylaxis for subsequent cycles in patients who had Grade 3 or 4 neutropenia in the previous treatment cycle.

In patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, consider discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg.

Instructions for Preparation and Administration

Administration:

  • Administer ADCETRIS only as a slow intravenous infusion. Do not mix with other medicines.

Reconstitution:

  • Follow proper handling and disposal procedures.
  • Use appropriate aseptic technique for reconstitution and preparation of the dose.
  • The required number of 50 mg vials of ADCETRIS should be determined based on the patient's weight and prescribed dose.
  • Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.
  • Direct the stream towards the wall of the vial while mixing the powder with saline and not directly at the powder.
  • Do not shake the solution but rather gently swirl it.
  • The reconstituted solution should be inspected for particulates and discoloration. It should be clear to slightly opalescent, colorless, and free of visible particulates.
  • After reconstitution, the solution should be diluted immediately into an infusion bag. If not diluted immediately, the solution should be stored at 2–8°C (36–46°F) and used within 24 hours of reconstitution. Any unused portion left in the vial should be discarded.

Dilution:

  • The required volume of 5 mg/mL reconstituted ADCETRIS solution should be calculated and withdrawn from the vial. The amount should then be added immediately to an infusion bag containing a minimum volume of 100 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer's Injection to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.
  • The bag should be gently inverted to mix the solution.
  • Following dilution, the ADCETRIS solution should be infused immediately. If not used immediately, the solution should be stored at 2–8°C (36–46°F) and used within 24 hours of reconstitution. The solution should not be frozen.

Side Effects caused by Brentuximab Vedotin:

Side Effects

Description

Common Side Effects

Nausea and vomiting

Feeling queasy or throwing up

Fatigue

Feeling very tired or weak

Fever

Elevated body temperature

Diarrhea

Loose or watery stools

Peripheral neuropathy

Numbness, tingling, or burning sensations in the hands and feet

Neutropenia

Low white blood cell count, which can increase the risk of infections

Rare Side Effects

Stevens-Johnson syndrome or toxic epidermal necrolysis

Rare but serious skin reactions that can cause severe blisters and peeling of the skin

Anaphylaxis

A severe allergic reaction that can cause difficulty breathing, hives, and swelling

Progressive multifocal leukoencephalopathy

Rare brain infection that can cause neurological symptoms such as confusion, difficulty speaking, and weakness

Pulmonary toxicity

Lung damage that can cause coughing, shortness of breath, and difficulty breathing

Side effects in clinical trials:

Type of Information

Value/Description

Note

Clinical trial results may not reflect real-world outcomes of the drug

Number of patients studied

160

Type of trials

Phase 2

Most common adverse reactions (≥20%) across both trials

Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting

Most common adverse reactions occurring in at least 10% of patients in either trial, regardless of causality

N/A

Contraindications to Adcetris:

Adcetris (brentuximab vedotin) is contraindicated in patients who are allergic to it, who have anaphylaxis and have other severe infusion-related reactions to Adcetris or any of its components.

It should also not be given to patients who have had a severe allergic reaction to other drugs containing the same active ingredient, brentuximab vedotin, or to any of the inactive ingredients in the drug.

Additionally, the use of Adcetris is not recommended in patients with severe hepatic impairment, as the safety and effectiveness of the drug have not been established in this patient population. It is also not recommended for use during pregnancy or in nursing mothers, as there is a potential risk of harm to the fetus or infant.

Precautions and warnings

The various risks and side effects associated with ADCETRIS treatment have been tabulated below:

Type of Risk/Side Effect

Description

Peripheral Neuropathy

Both sensory and motor neuropathy are common. It was observed in 54% of the patients in clinical trials.

Patients should be monitored for signs of neuropathy and the dose should be adjusted or the treatment should be discontinued.

Anaphylaxis and Infusion Reactions

Infusion-related allergic reactions can occur. Some reactions can be severe and manifest as angioedema and anaphylaxis.

Patients on treatment should be monitored for signs of allergic reactions.

Hematologic Toxicities

Severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS, which may lead to febrile neutropenia.

Monitor patients for complete blood counts prior to each dose and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia.

Serious Infections and Opportunistic Infections

Patients should be monitored for signs of infections including serious opportunistic infections. Appropriate treatment should be given immediately in case of an infection.

Tumor Lysis Syndrome

Tumor lysis syndrome can occur in patients with rapidly proliferating tumors and those with a high tumor burden. Appropriate hydration, uric acid-lowering treatment, and other therapies should be given before the infusion to avoid tumor lysis syndrome.

Increased Toxicity in the Presence of Severe Renal Impairment

Due to higher MMAE exposure, patients with severe renal impairment may experience more frequent and severe adverse reactions compared to those with normal renal function.

Avoid the use of ADCETRIS in patients with severe renal impairment (creatinine clearance (CLcr) <30 mL/min).

Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment

Avoid using Adcetris in patients with baseline hepatic impairment as the frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function.

Hepatotoxicity

Serious cases of liver injury have occurred in patients receiving brentuximab vedotin. Monitor liver enzymes and bilirubin.

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.

The diagnosis of PML should be considered in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities.

Serious Dermatologic Reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. Discontinue ADCETRIS and administer appropriate medical therapy if SJS or TEN occurs.

Embryo-Fetal Toxicity

There are no adequate and well-controlled studies of ADCETRIS in pregnant patients.

Patients who are prescribed ADCETRIS should be aware of the potential risks and side effects associated with the medication.

They should be closely monitored during treatment and promptly report any symptoms to their healthcare provider. Dose modification or discontinuation may be necessary in some cases to prevent adverse outcomes.

Drug interaction:

According to vitro data, it has been found that monomethyl auristatin E (MMAE) is both a substrate and an inhibitor of CYP3A4/5. Additionally, in vitro data has also suggested that MMAE functions as a substrate of the efflux transporter P-glycoprotein (P-gp).

Effect of Other Drugs on ADCETRIS:

Drug Interaction

Effect on ADCETRIS

Effect on MMAE

Monitoring Required

CYP3A4 Inhibitors

Increased exposure

Increased exposure by approximately 34%

Close monitoring for adverse reactions in patients receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS

CYP3A4 Inducers

Reduced exposure

Reduced exposure by approximately 46%

-

P-gp Inhibitors

Increased exposure

Increased exposure

Close monitoring for adverse reactions in patients receiving P-gp inhibitors concomitantly with ADCETRIS

Effect of ADCETRIS on Other Drugs:

  • No significant effects on CYP3A4 substrates and other CYP enzymes.

Use of Adcetris in specific populations:

Population/Condition

Information

Pregnancy

Pregnancy Category D. Avoid and inform the patient about fetal hazards.

Nursing Mothers

Limited data in this regard. Consider benefits and risks.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy not established in older people

Renal Impairment

Avoid in patients with severe renal impairment (CLcr <30 mL/min).

Due to higher MMAE exposure, ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function.

Hepatic Impairment

Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

The AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function, and the rate of ≥Grade 3 adverse reactions was 100% in patients with moderate and severe hepatic impairment.

Mechanism of action of Adcetris (Brentuximab vedotin):

Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of a chimeric IgG1 antibody directed against CD30 and a small molecule called MMAE, which is a microtubule-disrupting agent. The linkage between the antibody and MMAE is covalent.

Preclinical data suggest that ADCETRIS exhibits anticancer activity by binding to CD30-expressing cells, leading to internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. MMAE binds to tubulin and disrupts the microtubule network within the cell, which induces cell cycle arrest and apoptotic cell death.

QT/QTc Prolongation Potential:

Brentuximab does not prolong QT/QTc interval.

Pharmacokinetic Properties

Information

Absorption

Maximum concentrations of ADC were observed at the end of the infusion. The time to maximum concentration for MMAE ranged from approximately 1 to 3 days.

Distribution

In vitro, the binding of MMAE to human plasma proteins ranged from 68-82%.

Metabolism

In vivo data suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized, primarily via oxidation by CYP3A4/5. MMAE inhibits CYP3A4/5 but not other CYP isoforms.

Elimination

MMAE follows metabolite kinetics, with its elimination limited by its rate of release from ADC. Approximately 24% of the total MMAE administered as part of ADCETRIS was recovered in urine and feces over a 1-week period. The majority of the excreted MMAE was unchanged.

Additionally, steady state of ADC was achieved within 21 days with every 3-week dosing of ADCETRIS, and minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule.

MMAE exposures decreased with continued administration of ADCETRIS, with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses. In vitro, MMAE was a substrate of P-gp and was not a potent inhibitor of P-gp.

Adcetris in Pakistan:

Adcetris is not registered in Pakistan. People who are very needy acquire it by writing to the ministry to import it from neighboring countries on a humanitarian basis. Because of its non-availability, it is too costly and most people can not afford it.

You can check its availability and price in Pakistan here: https://wa.me/message/HV6M3JGTA6RJB1