Myocet
Encyclopedia
Myocet is a non-pegylated liposomal
Liposome
Liposomes are artificially prepared vesicles made of lipid bilayer. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules...

 doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

 made by Enzon Pharmaceuticals for Cephalon
Cephalon
Cephalon, Inc. is a U.S. biopharmaceutical company co-founded in 1987 by Dr. Frank Baldino, Jr., a pharmacologist and former scientist with the DuPont Company, who served as the company's chairman and chief executive officer until his death in December 2010...

 in Europe and for Sopherion Therapeutics in the United States and Canada. Myocet is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....

, but is not yet approved by the FDA for use in the United States. It is currently being studied by Sopherion Therapeutics in a pivotal phase III global registrational trial in concurrent combination with Herceptin (trastuzumab) and Taxol (paclitaxel) for treatment of HER2-positive metastatic breast cancer.

Research

Unlike Doxil (another formulation of liposomal doxorubicin), the Myocet liposome does not have a polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...

 (PEG) coating, and therefore does not result in the same prevalence of hand-foot syndrome. The minimization of this side effect may allow for one for one substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...

. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as Herceptin. There is an FDA black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...

 that Herceptin cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of Herceptin and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

 (CHF). Published phase II study results have shown that Myocet, Herceptin, and Taxol can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the on-going phase III trial for FDA approval.

Clinical pharmacology

Myocet has a different pharmacokinetic profile from doxorubicin, resulting in an improved therapeutic index (less cardiotoxicity and equal anticancer activity). The clearance of doxorubicin in patients receiving Myocet was found to be fivefold lower and the volume of distribution about tenfold lower than in patients receiving conventional doxorubicin. The half-life has been reported to be between 16-50 hours by at least 2 studies (which is significantly longer than conventional doxorubicin). The variability found in the half-life calculations could be due to confounding factors and dosage differences. These findings are in agreement with the theoretical advantage of using a liposomal enclosure for drug delivery. Liposomes are lipid bilayers with a hydrophobic external surface which should prevent it from passing through healthy capillaries thus decreasing the volume of distribution. Tumor capillaries are leaky allowing the liposome to enter the malignant tissue and this is the basis for its selectivity and pharmacokinetic properties.

Side Effects

In a randomized multi-center trial that recruited 224 patients to evaluate the cardiotoxicity of Myocet Vs. conventional doxorubicin, 2% of patients given Myocet developed congestive heart failure versus 8% with conventional doxorubicin. In this same study the most significant side effects of Myocet were myelosuppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...

specially thrombocytopenia, nausea and vomiting.
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