Download Liposomal doxorubcin

Liposomal formulations of
anthracyclines
By
Nortan Hashad
Under supervision of
Prof. Nashaat Lotfy
Professor of oncology
Liposomal formulations
Doxil®
Myocet®
DaunoXome®
Liposomal formulations
have been developed to
• Decrease the incidence of severe toxicity seen
with the conventional formulation.
• Taking advantage of the unique delivery
properties of liposomes and the cytotoxic effects
of free drug.
Doxil®
Uses the Stealth® liposome with
surface-bound methoxypolyethylene
glycol (MPEG) to avoid detection and
removal by the reticuloendothelial
system (RES).
Liposomes are effective drug carriers:
• Due to increased blood circulation time and small size which
allows penetration into areas of inflammation or malignant
disease.
• These areas tend to have leaky capillaries or enlarged spaces
within the lining of blood vessels which allows the liposome
to pass.
Liposomal formulation led to
Good results
Bad results
Efficacy
Cardiotoxicity
Extravasation
Multidrug resistance
Palmer-planter
erythema
Infusion syndrome
Efficacy
Long circulation time and slower clearance
led to allowing the use of smaller doses
and having a more prolonged time
interval.
Doxorubicin conventional:
60–90 mg/m2 every 3 weeks
Doxil ® :
50 mg/m2 every 4 weeks
Cardiotoxicity
Doxil ® is thought to have less cardiac
toxicities than conventional form.
1
Limited accumulation in healthy tissues like the
heart with a normal endothelial barrier.
2
Limited conversion to aglycones or secondary
alcohol metabolite (metabolites of acute
treatment with improved membrane diffusion
and reactive oxygen species mediated toxicity .
oDoxorubicinol is the primary metabolite in
chronic treatmentand may be a more potent
cardiotoxin than doxorubicin.
o The formation of doxorubicinol following
administration of pegylated liposomal
doxorubicin is dramatically reduced.
3
Extravasation
• Doxorubicin is a strong vesicant.
• Liposomal doxorubicin is irritant but not
vesicant upon administration.
Multidrug resistance
Liposomal formulation of doxorubicin is
less susceptible to tumor resistance via
MDR.
Palmer-planter erythema
•Also called hand-foot syndrome.
•Generally occurs when dose
intensity exceeds 10 mg/m2.
•Managed by reducing the dose
size and increasing cycle
duration.
1 Drug excretion in sweat and Local
pressure.
2 Exposure of feet to heat and friction
increases the amount of drug in the
capillaries and increases the amount of
drug leakage.
3 Liposomes stuck in small blood capillaries
in palms and soles leading to high local
conc.
Infusion syndrome
• Serious life-threatening anaphylactoid-like
infusion reaction seen with liposomal
doxorubicin.
• Not reported with conventional
doxorubicin.
• Slow infusion rate is recommended.
• This reaction is thought to be due to the
lipid component of the liposome or one of
its surface components.