90Y-Ibritumomab Tiuxetan

⁹⁰Yttrium-Ibritumomab is an antineoplastic agent indicated for non-Hodgkin’s lymphoma. ⁹⁰Y-Ibritumomab Tiuxetan, a monoclonal antibody, is currently unavailable in generic form due to its patented brand name, Zevalin. In February of 2002, Zevalin became the first ‘radioimmunotherapeutic’ pharmaceutical product to exist under FDA approval Zevalin is specifically indicated for previously untreated follicular non-Hodgkin’s lymphoma (NHL) as well as relapsed or refractory B-cell NHL.

Ibritumomab Tiuxetan	Metabolism	Product Information
Image Caption	CD 20 Receptor	CAS Number: 174722-31-7
IUPAC Name: Ibritumomab Tiuxetan Brand Name: Zevalin Generic: 90Y-Ibritumomab Tiuxetan/ 111In-Ibritumomab Tiuxetan	row 2, cell 2	Molecular Weight: 148 kD

Mechanism of Action

Zevalin is given in two stages: Ibritumomab Tiuxetan is first paired with elemental ¹¹¹Indium, followed by co-administration with radioactive ⁹⁰Yttrium. Ibritumomab Tiuxetan, the monoclonal antibody, is therefore coupled with a radioactively cytotoxic agent capable of directly targeting cancer cells. Once in the body, Ibritumomab Tiuxetan then binds with the CD20 receptor of B-cells, inducing apoptosis, or cell death, thereby reducing the growth of cancerous cells. The role of ¹¹¹Indium in Zevalin is to function as a tracer, determining whether the drug has been delivered to the correct tissues. After correct distribution is confirmed, ⁹⁰Yttrium provides specificity for cancer cells, exposing them to radioactive beta emission.

Dosage and Administration

Zevalin is a seven-day chemotherapy treatment. All treatments fall under the following FDA guidelines and scheduling:

Relapsed or Refractory B-cell NHL

Day 1: The patient receives 250mg/m² Rituximab intravenously. This is a common drug of chemotherapy. After four hours, the patient receives 5mCi ¹¹¹In-Ibritumomab Tiuxetan over 10 minutes.
Days 2-6: The patient receives a resting period in which medical imaging confirms or denies proper distribution, or biodistribution, of the drug.
Day 7: The patient again receives 250mg/m² Rituximab intravenously. After fours hours, the patient receives radioactive ⁹⁰Y-Ibritumomab Tiuxetan, substituting ⁹⁰Yttrium for ¹¹¹Indium.

Dosing for ⁹⁰Y-Ibritumomab Tiuxetan is based upon patient blood counts: Platelet levels of 100,000-149,000/m³ call for 0.3 mCi/kg over ten minutes, while counts of 150,000/m³ or more require 0.4 mCi/kg over ten minutes. The maximum dose of Zevalin is 32 mCi. For previously untreated NHL, however, platelet counts must be a minimum of 150,000/m³ and treatment must begin within six to twelve weeks following the final dose of the patient’s previous chemotherapy. ⁹⁰Y-Ibritumomab Tiuxetan is therefore infused at 0.4mCi/kg over ten minutes. Zevalin may also be adjusted to an eight or nine-day therapy given patient response: A physician may decide to administer ⁹⁰Y-Ibritumomab Tiuxetan on days seven, eight, or nine. Varying pre-medications are concomitantly administered and FDA required.

Medical Imaging

Radioactive imaging of Zevalin is required to be taken within 48 to 72 hours of administering its radioactive component. A great advantage of Zevalin therapy includes the ability to use this imaging to trace the drug throughout the lymphatic system. This is essential to determining proper biodistribution. After taking body images, or scintigrams, the following equation is used to determine radioactive exposure to varying tissues:

F_SPECT = (A_STD/A_O) x (C_TUM/C_STD)

Where A_O is the ¹¹¹Indium activity and A_STD its standard deviation, and C_TUM are the tumor SPECT counts and C_STD their standard deviations. This equation determines the fractional activity of particular components of the body and lymphatic system, such as the fraction of ¹¹¹In-Ibritumomab in a tumor versus the total activity of ¹¹¹In-Ibritumomab as a whole throughout the body. Multiple studies have determined total body absorption of Zevalin to be both safe and effective. The effective dose of a drug indicates the drug dose required to achieve a minimum 50% response in all patients. Medical imaging is therefore important to confirm not only drug delivery to the correct tissues, but also whether or not radioactive exposure achieves toxic effects. Indications of improper distribution or unsafe exposure require alteration of the dose, or discontinuation of the therapy itself.

Clinical Efficacy

Two main studies contributed to Zevalin's FDA approval, and have ultimately provided substantial support for the use of Zevalin in NHL. In the first study, an overall 74% response occurred in which 15% of patients attained a complete response to the treatment. In the second study, comparable outcomes were achieved: An overall 80% response occurred in which 16% of patients attained a complete response. Zevalin also displayed a greater efficacy than Rituximab alone, in which only a 56% response rate occurred. Event-free survival rates ranged from 8.5 to 28 months longer with Zevalin therapy than with patients’ most recently prior chemotherapeutic treatment. An average of 67% tumor shrinkage occurred. Clinical trials have further supported this data with overall responses ranging from 61.5% to 86%. In conclusion, throughout FDA approval, clinical trials, and drug phase testing, Zevalin was determined to have clinical efficacy, in which it

a) Provided higher overall and complete response rates than previous chemotherapy treatments,
b) Induced greater tumor shrinkage in solid cancer forms, and
c) Lengthened event-free survival rates following administration.

Contraindications

Zevalin should not be used while pregnant or breastfeeding, as it may cause damage to the unborn fetus or infant. Zevalin should not be combined with anticoagulants (ie. Warfarin, Aspirin, Heparin) as they will thin the blood and may cause excessive bleeding, a serious and potentially fatal adverse event. 80% of fatal therapies occurred within the first Rituximab infusion. Zevalin should not be given to patients with greater than 25% damaged lymphatic marrow.

Side Effects

Common side effects include thrombocytopenia and neutropenia, or low red blood cell and white blood cell counts, respectively. Thrombocytopenia of all grades clinically occurs in 62-95% of patients while neutropenia of all grades occurs in 45-77% of patients. Joint pain, infection, and fatigue are also prominent. Mild side effects include dizziness, hypoxia, anorexia, and gastrointestinal effects (ie. nausea, vomiting, diarrhea, abdominal pain). Severe adverse events include extreme hematological toxicity, immune system infection due to vulnerability, heart attack, uncommon dermatological effects, and overexposure to radiation.

Expense

A single dose of Zevalin costs ranges $22,000 to $24,000 in a hospital setting, making it the most expensive single-dose drug on the market. This treatment, however, comprises a full therapy (seven to nine days), whereas most chemotherapy regimens consist of multiple drugs on varying days. A typical chemotherapy regimen costs a patient on average between $20,000 and $30,000, making Zevalin a somewhat middle-of-the-road regimen in terms of chemotherapy financial expense.

References

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