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   Mechanism of action
   Pharmacokinetics
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MOLECULES OF THE MILLENNIUM
Year : 2004  |  Volume : 36  |  Issue : 6  |  Page : 390-391
 

Trastuzumab


Department of Pharmacology, Spartan University of Health Sciences, School of Medicine, Post box # 324, Vieux fort, St.Lucia, Guyana

Correspondence Address:
Department of Pharmacology, Spartan University of Health Sciences, School of Medicine, Post box # 324, Vieux fort, St.Lucia, Guyana
[email protected]



How to cite this article:
Beedimani R S. Trastuzumab. Indian J Pharmacol 2004;36:390-1


How to cite this URL:
Beedimani R S. Trastuzumab. Indian J Pharmacol [serial online] 2004 [cited 2021 Oct 19];36:390-1. Available from: https://www.ijp-online.com/text.asp?2004/36/6/390/13518


Trastuzumab is a DNA recombinant-derived immune protein and the first humanized monoclonal antibody, which is approved by FDA for the treatment of HER 2/neu positive metastatic breast cancer. Trastuzumab in combination with paclitaxel is indicated in patients with metastatic breast cancer whose tumors overexpress the HER 2 protein and who have not received chemotherapy for their metastatic disease. The drug as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER 2 protein and who have one or more chemotherapy regimens for their metastatic disease.

Fluorescence In Situ Hybridization (FISH) is a method used to determine women with HER 2/ neu overexpression in metastatic breast cancer, which are likely to benefit from trastuzumab. The FISH test is considered the most accurate test for the determination of HER 2/ neu gene malfunction. "FISH Positive" means that excessive amounts of the HER 2/ neu cancer gene are present and the cancer tend to lie at the more aggressive end of the spectrum, but respond best to trastuzumab. "FISH negative" means that normal amounts of the HER 2/ neu cancer gene are present and the patient is not likely to benefit from trastuzumab.


  Mechanism of action Top


Trastuzumab is considered to act in three different ways:

(a) By binding to the HER 2 receptors on the tumor cell surface, it blocks HER 2 receptor, hence the tumor cell is not activated to grow and divide.
(b) The natural killer cells detect trastuzumab attached to the HER 2 receptor on the tumor cells as abnormal and kill them. Thus it stimulates and signals the immune system to destroy breast cancer cells. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC).
(c) Trastuzumab and the conventional anti-cancer agents act in a different manner, but when given together, the two drugs are synergistic in nature and more effectively decrease the tumor size, increase the median time of disease progression and also improve the one year survival rates.


  Pharmacokinetics Top


Intravenous infusions of 10 - 500 mg doses once weekly have dose-dependent pharmacokinetics. With a loading dose of 4 mg/kg and weekly maintenance dose of 2 mg/kg, a mean half-life of 5.8 days was seen. Mean half-life increased, and clearance decreased at 10 mg and 500 mg dose levels respectively. Disposition of trastuzumab is not altered based on age or serum creatinine up to 2 mg/dl. No formal drug interaction studies were performed. The volume of distribution is 44 mg/kg. Given weekly at the highest dose of 500 mg, the mean peak serum concentration was 377 g/ml.

Adverse effects and precautions

Fever, chills, nausea, diarrhea, headache, dizziness, rashes, vomiting, anemia, fatigue, hair loss, pulmonary infiltrates, hypoxia and pulmonary insufficiency were reported. Trastuzumab can result in severe hypersensitivity reactions like anaphylaxis usually within 24 h of administration. Trastuzumab administration can result in the development of ventricular dysfunction and congestive cardiac failure. Discontinuation of Trastuzumab should be strongly considered in patients who develop a clinically significant decrease in left ventricular function. The incidence and severity of cardiac dysfunction was particularly high in patients who received trastuzumab in combination with anthracyclines (doxorubicin) and cyclophosphamide.


  Preparation and dosage Top


Trastuzumab is supplied as a lyophilized, white to pale yellow sterile powder containing 440 mg per vial under vacuum. Reconstitution with 20 ml of the supplied bacteriostatic water for injection (BWFI) USP, containing, 1.1% benzyl alcohol as preservative, yields 21 ml of a multi-dose solution containing 21 mg/ml trastuzumab, at a pH of 6. A vial of trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when stored at 2-8o C (36-46o F), and the solution can be preserved for multiple uses.

If the patient has known hypersensitivity to benzyl alcohol, trastuzumab must be reconstituted with sterile water for injection (SWFI). Trastuzumab, which has been reconstituted, with SWFI must be used immediately and the unused portion discarded. The reconstituted preparation results in a colorless to pale yellow transparent solution. Use of other reconstitution diluents should be avoided. Dextrose 5% solution can be used. Trastuzumab can only be given intravenously and on an outpatient basis at 4 mg/kg loading dose over 90 minutes and with subsequent weekly doses of 2 mg/kg over 30 minutes. Trastuzumab is usually given in six doses and can be taken indefinitely to prevent the relapse of breast cancer.

Trastuzumab and chemotherapy

Trastuzumab is often given in combination with other conventional anti-cancer drugs at the same time or in sequence. The anti-cancer drugs which are in clinical trial for combination with trastuzumab include Paclitaxel, Docetaxel, CMF (Cyclophosphamide, Methotrexate and Fluorouracil), Vinorelbine, Gemcitabine, Capecitabine, Carboplatin, Anastrozole and Letrozole.

Trastuzumab when used against metastatic breast cancer with overexpression of HER 2/neu gene is a promising novel molecule and a unique biological therapy with objective response of 20-25% when used with one of the chemotherapy regimens, and of 40% when used in combination with paclitaxel.

Sources

www.breastcancer.org
www.herceptin.com
www.cancernews.com
www.fda.gov 

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