Liposomal formulations of anthracyclines

ByNortan Hashad

Under supervision of

Prof. Nashaat LotfyProfessor 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.

Uses the Stealth® liposome with surface-bound methoxypolyethylene glycol (MPEG) to avoid detection and removal by the reticuloendothelial system (RES).

Doxil®

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 resultsEfficacy

CardiotoxicityExtravasation

Multidrug resistance

Bad results

Palmer-planter erythema

Infusion syndrome

EfficacyLong 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 weeksDoxil ® :50 mg/m2 every 4 weeks

Cardiotoxicity Doxil ® is thought to have less

cardiac toxicities than conventional form.

1Limited accumulation in healthy tissues like the heart with a normal endothelial barrier.

2Limited conversion to aglycones or secondary alcohol metabolite (metabolites of acute treatment with improved membrane diffusion and reactive oxygen species mediated toxicity .

3oDoxorubicinol 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.

Extravasation• Doxorubicin is a strong vesicant.• Liposomal doxorubicin is irritant but

not vesicant upon administration.

Multidrug resistanceLiposomal 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.

1Drug excretion in sweat and Local pressure.

2Exposure of feet to heat and friction increases the amount of drug in the capillaries and increases the amount of drug leakage.

3Liposomes 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.