Monday, October 22, 2018

Doxorubicin Liposomal: An Improvement on Chemotherapy

Image result for doxorubicin liposomal
Figure 1Graphic depiction of the structure of Doxorubicin Liposomal.
Retrieved from https://www.researchgate.net/figure/Schematic-of-
PEGylated-liposomal-doxorubicin-Doxil-structure-Doxorubicin-inset_fig1_266380943
Doxorubicin History and Function
Doxorubicin liposomal is a chemotherapeutic agent.  It consists of an antineoplastic drug encapsulated in a liposomal envelope.  The antineoplastic drug was first released as Adriamycin.  Doxorubicin is used most often against solid tumors and lymphomas.  It is derived from a natural product produced from a mutated strain of Streptomyces bacteria created by researchers in 1969[1].  It was adapted from another compound identified by a French pharmaceutical company in the 1950s[1].  The drug works through inhibiting topoisomerase II which works to separate strands of DNA before transcription[2]. Inhibiting this enzyme makes it functionally impossible for the cells to divide, thus stopping the growth of the cancer tumor.

Doxorubicin Side Effects
But, drugs do not always only target cancer cells.  This was the case with doxorubicin; high non-specific toxicity limited the maximum dosing and increased side effects felt by patients.  This is common with cytotoxic agents and chemotherapeutics.  One of the most serious side effects caused by treatment with doxorubicin was congestive heart failure, but like most chemotherapeutic agents it heightened the possibility for infection, especially bowel infections, nausea, fatigue, and other symptoms[3]. Also, because of this drug’s tendency to darken skin, nails, and urine, it is nicknamed the “red devil”[3].

Liposomal Formulation
In order to combat these negative effects, researchers began coupling active pharmaceutical ingredients with liposomal membranes.  The first drug-membrane combo was an anti-fungal agent released in 1990[4].  The first approved anticancer liposomal complex was released in 1998[4].  Encasing the drug in a lipid complex has several advantages and improves drug function in multiple ways.  For example, because the cell membrane is also a lipid bilayer, it can increase cellular penetration[4].  Also, biomarkers can be added to the outside of the envelope to better target exclusively cells of a patient’s specific cancer[4].  Increasing the specificity of the drug decreases patient side-effects and increases drug efficacy, both important in the development of new cancer treatments.
Incasing doxorubicin in a liposomal membrane “dramatically” increased patient tolerance to the drug, meaning the drug becomes safer at larger doses[5].  This allows a larger amount of drug to target the tumor per treatment, hopefully decreasing treatment length.  Studies have also shown that the addition of the lipid bilayer increases the uptake of doxorubicin into cancer cells[4, 6].

Regulatory Information
Doxorubicin Liposomal is classified as an anthracycline which is a class of chemotherapeutic agents derived from Streptomyces bacteria [7]. It is only available through a prescription and only administered intravenously in a medical clinic. It is pregnancy category D denoting that it has been documented to cause significant fetal harm, but may be warranted in life-threatening situations as no safer alternatives may exist [8]. In 2004 Doxil® was also designated as an Orphan Drug for treatment of multiple myeloma in combination with bortezomib after at least one prior treatment regimen [9].

Commercialization
The Liposomal formulation of doxorubicin was developed by Liposome Technology Inc. and was approved in by the FDA in 1995 for treatment of a number of cancers [10]. It was sold under the brand name Doxil® by Janssen Products, L.P., a Johnson & Johnson Company from 1995 until 2011. In July of 2011, Ben Venue Laboratories, a contract manufacturer responsible for the production of Doxil®, halted production activities due to quality control concerns [11]. The Food and Drug Administration found system-wide deficiencies in good manufacturing practices during a routine facilities inspection [12]. Ben Venue Laboratories was unable to adequately address these manufacturing discrepancies, and the facility was permanently shut down in 2013 [13]. In the third quarter of 2011, sales of Doxil® dropped 87% due to the drug shortage caused by this production shutdown [14].  
This drug shortage persisted for nearly three years until, after the patent for doxorubicin liposomal [15] expired, Caraco Pharmaceutical Laboratories Ltd. Filed an Abbreviated New Drug Application that the Food and Drug Administration approved in 2013 [16]. This ANDA allowed Caraco to import a bioequivalent doxorubicin liposomal product called Lipodox® from Sun Pharma Global FZE which is based out of India [16]. Sun Pharma Global FZE is a multi-national corporation which in 2014 had a total sales revenue of USD 526,965,344 [17]. Their monopoly of the United States doxorubicin liposomal market did not last long, however, as Janssen Products, L.P. filed a Supplemental New Drug Application (sNDA) to approve a new manufacturing site for Doxil® which was approved by the Food and Drug Administration in 2015 [9]. This allowed Janssen to begin producing Doxil® in an Italy facility managed by GlaxoSmithKline. In large part because of Doxil®’s return to the market, Sun Pharma Global FZE saw a downturn in profits, with a revenue of USD 353,701,093 in 2015 [17]. Both Dosil® and Lipodox® are currently available in the US market.

Intellectual Property  
There are several patents relevant to the liposomal formulation of doxorubicin. The patent for doxorubicin liposomal was held by Alberto Gabizon, Eliezer Kedar, and Yechezkel Barenholz of Liposome Technology Inc., and expired in 2010 [15]. Other relevant patents include “Methods of forming protein-linked lepidic microparticles, and compositions thereof” held by the University of California [18]. This details how the lipid bilayer that encases the doxorubicin is assembled. The Japanese patent “Dipyrithione Doxil host Hue- door NMRI contrast agent” details a method of measuring both drug loading into the liposomal envelope and drug delivery into the tissue of interest [19].
Additionally, the brand Doxil® is under trademark registered to Janssen Products, L.P.. The trademark was initially registered in 1993, and has been renewed twice [20]. Lipodox® is also under trademark registered to Sun Pharma Global FZE. The trademark for Lipodox® was only registered in 2018 [21].


References
1.         Cassinelli, G., The roots of modern oncology: from discovery of new antitumor anthracyclines to their clinical use. Tumori, 2016. 2016(3): p. 226-35.
2.         Thorn, C.F., et al., Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics, 2011. 21(7): p. 440-6.
3.         Side effects of doxorubicin (Adriamycin). 2017 18 September 2017 [cited 2018; Available from: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/doxorubicin/side-effects.
4.         Slingerland, M., H.J. Guchelaar, and H. Gelderblom, Liposomal drug formulations in cancer therapy: 15 years along the road. Drug Discov Today, 2012. 17(3-4): p. 160-6.
5.         Muggia, F.M., Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin Cancer Res, 1999. 5(1): p. 7-8.
6.         Goren, D., et al., Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. Clin Cancer Res, 2000. 6(5): p. 1949-57.
7.         NCI, Anthracycline, in Dictionary of Cancer Terms
8.         Medscape. Doxorubicin Liposomal Available from: https://reference.medscape.com/drug/doxorubicin-liposomal-342121#6.
9.         Janssen Products, L.P., NDA 50-718/S-50, C.f.D.E.a. Research, Editor. 2015, Food and Drug Administration
10.       Barenholz, Y., Doxil(R)--the first FDA-approved nano-drug: lessons learned. J Control Release, 2012. 160(2): p. 117-34.
11.       Loftus, P., J&J Is Short of Cancer Drug Doxil, in The Wall Street Journal 2011: Web.
12.       Services, D.o.H.a.H., Ben Venue Lab Inspection 05022011. 2011, Food and Drug Administration
13.       Loffelsend, J., Ben Venue Laboratories, Inc. to Cease Production 2012, Boehringer Ingelheim
14.       Taylor, N. Shortages to Worsen after Ben Venue Suspends Manufacture 2011.
15.       Alberto A. Gabizon, e.a., Combines chemo-immunotherapy ith liposmal drugs and cytokines, U.P. Office, Editor. 1998.
16.       FZE, S.P.G., ANDA 203263, C.f.D.E.a. Research, Editor. 2013, Food and Drug Administration Web
17.       FZE, S.P.G., Financial Statements 2015.
18.       Demetrios Papahadjopoulos, e.a., Methods of forming protein-linked lipidic microparicles, and compositions thereof U.P. Office, Editor. 1996.
19.       Dipyrithione Doxil host Hue- door nmri contrast agent J.P. Office, Editor. 1988.
20.       Office, U.S.P.a.T., Doxil in Trademark Electronic Search System 1993: Web
21.       Office, U.S.P.a.T., Lipodox, in Trademark Electronic Search System 2018.


No comments:

Post a Comment