Myocet

Myocet^[1] is a non-pegylated liposomal doxorubicin made by Enzon Pharmaceuticals for Cephalon 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, 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 (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. 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 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 (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.^[2] 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^[3] 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.^[4] In this same study the most significant side effects of Myocet were myelosuppression specially thrombocytopenia, nausea and vomiting.

See also

• Doxorubicin
• Nanoparticle
• Liposome

References

1. ^ "Liposomal doxorubicin (Caelyx, Myocet)". Macmillan Cancer Support. April 1, 2009. http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/Individualdrugs/Liposomaldoxorubicin.aspx. Retrieved 2009-11-27. 
2. ^ Mross K, Niemann B, Massing U, et al. (December 2004). "Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study". Cancer Chemother. Pharmacol. 54 (6): 514–24. doi:10.1007/s00280-004-0825-y. PMID 15322827. 
3. ^ Nagy JA, Chang SH, Dvorak AM, Dvorak HF (March 2009). "Why are tumour blood vessels abnormal and why is it important to know?". Br. J. Cancer 100 (6): 865–9. doi:10.1038/sj.bjc.6604929. PMC 2661770. PMID 19240721. http://www.nature.com/bjc/journal/v100/n6/full/6604929a.html. 
4. ^ Harris L, Batist G, Belt R, et al. (January 2002). "Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma". Cancer 94 (1): 25–36. doi:10.1002/cncr.10201. PMID 11815957.