Daclizumab Imunosuppressant Drug

INTRODUCTION: Daclizumab (trade name Zinbryta) is a therapeutic humanized monoclonal antibody used for the treatment of adults with relapsing forms of multiple sclerosis. Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T cells.

It was formerly marketed under the trade name Zenapax to prevent acute rejection in people with kidney transplants along with cyclosporine and corticosteroids but marketing of the drug for that purpose was discontinued in 2009 due to lack of market demand.

THERAPEUTIC USES:

Preventing organ rejection in kidney transplant patients in combination with other medicines. It may also be used for other conditions as determined by your doctor.

Daclizumab is a monoclonal antibody and immunosuppressive agent. It works by blocking the activation of the immune system, which decreases the risk of the body rejecting a transplanted organ.

PRECAUTIONS:

Some medical conditions may interact with daclizumab. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding

• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

• if you have allergies to medicines, foods, or other substances

• if you have diabetes or an infection

SIDE EFFECTS:

In clinical trials for MS, there were no treatment-related deaths or increased risk of cancer; side effects that occurred more frequently with daclizumab versus interferon included infections (65% versus 57%), skin rashes (37% versus 19%) and liver complications (approximately 18% versus 12%

These events included:

Gastrointestinal System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not food-related;

Metabolic and Nutritional: edema extremities, edema;

Central and Peripheral Nervous System: tremor, headache, dizziness;

 Urinary System: oliguria, dysuria, renal tubular necrosis;

Body as a Whole - General: posttraumatic pain, chest pain, fever, pain, fatigue;

 Autonomic Nervous System: hypertension, hypotension, aggravated hypertension;

 Respiratory System: dyspnea, pulmonary edema, coughing;

 Skin and Appendages: impaired wound healing without infection, acne;

Psychiatric: insomnia;

Musculoskeletal System: musculoskeletal pain, back pain;

Heart Rate and Rhythm: tachycardia;

Vascular Extracardiac: thrombosis; Platelet,

Bleeding and Clotting Disorders: bleeding;

Hemic and Lymphatic: lymphocele.

DRUG-DRUG INTERACTIONS:

• Cyclosporine + drug  = increase in side effects, synergistic effect.

• Drug + corticosteroids = increase side effect of the drug

• In case of Cardiac Transplant + drug = may increase the mortality

MECHANISM OF ACTION:

Daclizumab functions as an IL-2 receptor antagonist that binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding. Daclizumab binding is highly specific for TAC, which is expressed on activated but not resting lymphocytes. Administration of  daclizumab  inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.

While in the circulation, daclizumab impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal daclizumab after is cleared is unknown.

PHARMACODYNAMICS:

In vitro and in vivo data suggest that serum levels of 5 to 10 µg/ml are necessary for saturation of the Tac subunit of the IL-2 receptors to block the responses of activated T lymphocytes. At the recommended dosage regimen, daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 90 and 120 days post transplant, respectively in pediatric and adult patients. The duration of clinically significant IL-2 receptor blockade after the recommended course of daclizumab is not known. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine release syndrome has not been observed after daclizumab administration.

PHARMACOKINETICS:

In clinical trials involving renal allograft patients treated with a 1 mg/kg IV dose of ZENAPAX (daclizumab) every 14 days for a total of five doses, peak serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/ml) and fifth dose (32 22 g/ml). The mean trough serum concentration before the fifth dose was 7.6±4.0 µg/ml.

Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (45-year-old male Caucasian patient with a body weight of 80 kg and no proteinuria): systemic clearance = 15 mL/hour, volume of central compartment = 2.5 liter, volume of peripheral compartment = 3.4 liter.

The estimated terminal elimination half-life for the reference patient was 20 days (480 hours), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for the 123 patients included in the population analysis.

The influence of body weight on systemic clearance supports the dosing of (daclizumab) on a milligram per kilogram (mg/kg) basis. For patients studied, this dosing maintained drug exposure within 30% of the reference exposure.

Covariate analyses showed that no dosage adjustments based on age, race, gender or degree of proteinuria, are required for renal allograft patients. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 15% and 27%, respectively.

REFERENCE: Tripathi K.D; "Essentials of medical pharmacology" Page no-878,884