Overview of PLD (Caelyx)

Overview of PLD

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Introduction to doxorubicin
Overview of liposomes
Pegylated liposomal doxorubicin (Caelyx)
Toxicity profile of Caelyx

Introduction to Doxorubicin
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Doxorubicin: Development
First isolated from
Streptomyces peucetius
found predominantly in
soil and decaying
vegetation
Member of the
anthracycline family
Highly effective against
many solid tumours and
haematological cancers
Doxorubicin
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Doxorubicin: Development
Clinical use of doxorubicin was hampered because of
drug-induced toxicity and drug resistance

Modify formulation to
reduce toxicity

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Modify method of
delivery

Doxorubicin: Mechanism of Action

The precise mechanism of action of anthracyclines is
not completely understood
Doxorubicin:
interferes with topoisomerase II molecules, which
prevents religation of DNA
impaired protein synthesis
double-stranded DNA breaks
apoptosis
generates free radicals, which attack and damage
DNA, RNA, lipids and proteins

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Doxorubicin Safety Limitations:

Cardiotoxicity
Caused by free radical damage to the myocytes
Acute cardiomyopathy during/immediately after a
single dose of doxorubicin
Chronic cardiomyopathy result of cumulative build
up of doxorubicin
Late-onset cardiomyopathy may occur up to 15
years after treatment1
Necessitates a reduced dose of doxorubicin
1. Lipshultz SE, Lipsitz SR, Mone SM et al. Female sex and drug abuse as risk factors for late cardiotoxic effects of doxorubicin
therapy for childhood cancer. N Engl J Med 1995; 332:17338-43.
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Doxorubicin Safety Limitations:

Other Toxicities

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Myelosuppression
Alopecia
Acute nausea and vomiting
Ulceration and necrosis of the colon
Neuropathy
Hepatic Dysfunction

Doxorubicin: Rationale for liposomal

formulations

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Drug release and

bioavailability

Changes
Changes in
in drug
drug
biodistribution
biodistribution

Reduces clearance by the

renal system

Reduces exposure to
heart/sensitive tissues

Fewer side effects

Increase accumulation
in tumour cells

Overview of Liposomes
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Phospholipids: What are they?

Hydrophilic head
carries electrical charge
attracted to water
repelled by lipid
Hydrophobic tail
no electrical charge
attracted to lipid
repelled by water

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Phospholipids: What are they?

Agitation results in liposome formation

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Phospolipid Bilayers & Nature

Aqueous phase

Lipid
(cholesterol)

Aqueous phase

Cell membranes are phospholipid bilayers arranged like this

allows cells to have aqueous cytoplasm
to exist in an aqueous environment
but to keep inside and outside separate
These properties are exploited in liposomes
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Phospholipids & Liposomes

Phospholipids naturally align like this at water:lipid interfaces

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Liposomes: What are they?

Bilayered structures made
from amiphipathic
phospholipids
Sizes range from 0.02510m diameter

Cross sectional view of a liposome

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Liposomes: Phospholipid Modifications

Three main sections: head group, glycerol backbone, and

hydrophobic tail
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Liposomes: Preparation
Can be created using various laboratory and industrialscale techniques
Uses the natural hydrophilic/hydrophobic properties of the
phospholipids
Requires the input of energy/solvent to disperse the
phospholipids
Must be sterilised before use

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Liposomes: Approved Liposomal

medications
Drug name

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Indications/target

Caelyx

Metastatic breast cancer, advanced ovarian

cancer, multiple myeloma, and AIDS-related
Kaposis sarcoma

Marqibo-vincristine

Adult patients with acute lymphoblastic

leukaemia

DaunoXome

Advanced HIV-associated Kaposis sarcoma for

the first-line use

AmBisome

Fungal infection and visceral leishmaniasis

Amphocil

Invasive aspergillosis and leishmaniasis

ABELCET

Antifungal antibiotic for invasive fungal

treatment

Depocyt

Lymphomatous meningitis

Liposomes: Impact on anthracycline

delivery1

Reduced volume of distribution and clearance

Prolonged half-life
Limited conversion to secondary metabolites
Preferential accumulation in tumours
Prolonged release within the tumour environment
Partial circumvention of tumour resistance
Limited accumulation in healthy tissues

1. Minotti. G, Menna P, Salvatorelli E, et al. Anthracyclines: Molecular advances and pharmacologic developments in
antitumour activity and cardiotoxicity. Pharmacol Rev 2004; 56: 185-229.
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Liposomes: Pharmacokinetics
Comparison of the pharmacokinetics of PLD with free
doxorubicin.
Parameter measured after a 50mg/m2
dose

PLD

Free doxorubicin

Half-life
First exponent of elimination
Second exponent of elimination

1.4
46

0.06
10.4

Volume of distribution (Vd; litres)

5.9

254

Clearance (CL; hours/litre)

0.09

25.3

1. Gabizon A, Goren D, Cohen R et al. Development of liposomal anthracyclines: From basics to clinical applications. J Control
Relwase 1998; 53: 275-9
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Liposomes: Benefits
Encapsulation affects the pharmacokinetic and
biodistribution properties of medicines
dependant on the lipids used in liposome
formation, liposome size, and overall composition
difficult to optimise these factors
Aim of encapsulating doxorubicin is to reduce its
toxicity and increase its tumour specificity
But there is more

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Stealth Liposomes
Liposomes can be targets
for the immune system
Stealth liposomes
have hydrophilic polymers
attached to their surface
evade the immune system
Caelyx was the first stealth
liposome formulation

Stealth liposome
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Stealth Liposomes: Polyethylene Glycol

Good biological and chemical properties

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biocompatibility
solubility
lack of toxicity
very low immunogenicity/antigenicity
good kinetics

Can be incorporated into lipid bilayer

Positive data for liposome technology

Stealth Liposomes: Advantages

Plasma stability and long plasma resistance times
Extravasation of liposomes through gaps in the
endothelium of tumour vessels
Release of encapsulated doxorubicin following
extravasation
Tumour cell penetration and cytotoxicity

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Stealth Liposomes: Immune response

Liposomes are removed from the body by:
Detection by plasma proteins
Clearance by the reticuloendothelial system
Filtration by the kidney cells

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Pharmacological Basis for PLD Action

Key attributes: Pegylation, stable drug retention & optimal size
Evade RES
Long circulation
Avoid healthy tissues

Extravasation
Tumor accumulation

Slow drug release

Enhanced efficacy
Reduced toxicity

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Pegylated lipsomal doxorubicin (Caelyx)

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PLD
Doxorubicin hydrochloride encapsulated in the water phase
of liposomes with surface bound methoxypolyethylene
glycol (MPEG)
Cytotoxic anthracycline antibiotic
Intercalates into the DNA resulting in DNA, RNA, and
protein synthesis

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PLD: Licensed indications

Metastatic breast cancer, where there is increased cardiac
risk
Advanced ovarian cancer in women who have failed a firstline platinum-based chemotherapy regimen
Treatment (with bortezomib) of progressive multiple
myeloma in patients who have received at least one prior
therapy and who have already undergone or are unsuitable
for bone marrow transplant
AIDS-related Kaposi's sarcoma in patients with low CD4
counts and extensive mucocutaneous or visceral disease

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PLD: Administration
Breast and ovarian cancer
Caelyx is administered intravenously at a dose of
50 mg/ml2 once every four weeks for as long as the
disease does not progress and the patient continues to
tolerate treatment

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PLD: Administration
Multiple Myeloma
Caelyx is administered at 30 m mg/ml2 on day 4 of the
bortezomib 3-week regimen as a 1-h infusion given
immediately after the bortezomib infusion
Caelyx dosing should be repeated as long as patients
respond satisfactorily and tolerate treatment
Day 4 dosing of both medicinal products may be delayed
up to 48 h as medically necessary
Doses of bortezomib should be at least 72 h apart

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PLD: Administration
Kaposis sarcoma
Caelyx is administered intravenously at 20 mg/ml2 every 2
3 weeks.
Treatment of patients for 23 months is recommended to
achieve a therapeutic response and should be continued
as needed
The dose of Caelyx is diluted in 250 ml 5% (50 mg/ml)
glucose solution for infusion and administered by
intravenous infusion over 30 minutes

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PLD: Patients exceptions1

Patients with impaired hepatic function
Patients with impaired renal function
Patients with AIDS-related Kaposi's sarcoma with
splenectomy
Paediatric patients
Elderly patients
Pregnant and breast-feeding women

1. Summary of Product Characteristics

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Caelyx: Pharmacodynamic properties

Non-inferiority to native doxorubicin
Significantly lower cardiotoxicity than native doxorubicin
Improved survival rate to topotecan in ovarian cancer
patients following failure of first-line platinum-based
chemotherapy
Increased safety and efficacy when used in combination
with bortezomib compared to bortezomib alone

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PLD: Pharmacodynamic properties

Pharmacokinetic properties of DLP1
Patients (n=120)
Dose range (mg/m2)
Intrinsic clearance (l/h/m2)
Volume of distribution (l/m2)
Half-life (h)

1. Summary of Product Characteristics

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10-60
0.030 (range 0.008-0.152)
1.931 (0.96-3.851)
73.9 (24-231)

Toxicity profile of PLD

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Toxicity: Preclinical data

Repeat dose studies in animals revealed that the toxicity
profile of Caelyx is very similar to that reported in humans
who receive long-term infusions of standard doxorubicin
hydrochloride

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PLD: Palmer-plantar erythrodysaesthesia

(PPE)
Also known as hand-foot syndrome
Small amounts of Caelyx leak into the capillaries in the
palms of hands and soles of feet
Results in redness, tenderness, and pealing skin
Generally seen after 23 treatment cycles
Can be managed with pyridoxine and corticosteroids
Requires an altered dosing pattern for Caelyx
administration

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PLD: Cardiotoxicity
Caelyx is associated with significantly reduced cardiotoxicity1
Patients (n)
PLD
(n=254)

Doxorubicin
(n=255)

Cardiotoxicity (decreased LVEF)

With signs/symptoms of CHF
Without signs/symptoms of CHF

10
0
10

48
10
38

Signs/symptoms of CHF alone

1. OBrien MER, Wigler N, Inbar M et al. Reduced cardiotoxicity and comparable efficacy in a phase Iii trial of pegylated liposomal doxorubicin
HCI (CaelyxTM/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004; 15: 4409.
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PLD: Other toxicities

Toxicities of Caelyx compared with native doxorubicin1
Toxicity Measure

PLD

Doxorubicin

Vesicant effect

+/-

+++

Infusion reaction

+*

Nausea/vomiting

+/-

++

Myelosuppression

+ (no grade
4)

+++

+++

++

+++

Stomatitis/mucositis
Alopecia

* Drip-rate and pre-medication dependent.

1. Solomon R and Gabizon AA. Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal doxorubicin. Clin Lymph
Myeloma 2008; 8: 2132.
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