Figure 1: Graphic 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 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