Download Doxorubicin liposome

Doxorubicin liposome
Trade Names
Doxil
Classification
Antitumor antibiotic
Category
Chemotherapy drug
Drug Manufacturer
Ortho-Biotech
Mechanism of Action
Liposomal encapsulation of doxorubicin.
Protected from chemical and enzymatic degradation, reduced plasma
protein binding, and decreased uptake in normal tissues.
Penetrates tumor tissue into which doxorubicin is released.
Intercalates into DNA resulting in inhibition of DNA synthesis and
function.
Inhibits transcription through inhibition of DNA-dependent
RNA polymerase.
Inhibits topoisomerase II by forming a cleavable complex with DNA
and topoisomerase II. This creates uncompensated DNA helix torsional
tension, leading to eventual DNA breaks.
Formation of cytotoxic oxygen free radicals results in single- and
double-stranded DNA breaks and subsequent inhibition of DNA
synthesis and function.
Mechanism of Resistance
Increased expression of the multidrug-resistant gene with elevated
P170 protein levels. This leads to increased drug efflux and decreased
intracellular drug accumulation.
Decreased expression of topoisomerase II.
Mutation in topoisomerase II with decreased binding affinity to drug.
Increased expression of sulfhydryl proteins, including glutathione
and glutathione-dependent proteins.
Absorption
Distribution
Mainly confined to the intravascular compartment. In contrast to parent
drug, doxorubicin, which has a large V d (700–1,100 L/m 2 ), liposomal doxorubicin
has a small V d (2 L/m 2 ). Does not cross the blood-brain barrier. Binding
to plasma proteins has not been well characterized.
Metabolism
Plasma clearance of Doxil is slower than that of doxorubicin, resulting in
AUCs that are significantly greater than an equivalent dose of doxorubicin.
Prolonged terminal half-life of about 55 hours.
Indications
AIDS-related Kaposi’s sarcoma—Used in patients with disease
that has progressed on prior combination chemotherapy and/or in
patients who are intolerant to such therapy.
Ovarian cancer—Metastatic disease refractory to both paclitaxel and
platinum-based chemotherapy regimens.
Multiple myeloma—FDA-approved in combination with bortezomib
in patients who have not previously received bortezomib and who
have received at least one prior therapy.
Dosage Range
Kaposi’s sarcoma: 20 mg/m 2 IV every 21 days.
Ovarian cancer: 50 mg/m 2 IV every 28 days.
Multiple myeloma: 30 mg/m 2 IV on day 4 after bortezomib, which is
administered at 1.3 mg/m 2 IV on days 1, 4, 8, and 11, every 21 days.
Drug Interactions
None well characterized to date.
Special Considerations
Liposomal doxorubicin should not be substituted for doxorubicin on
a mg-per-mg-basis and should be used only where indicated.
Use with caution in patients with abnormal liver function. Dose
reduction is required in the setting of liver dysfunction.
Infusions of liposomal doxorubicin should be given at an initial rate
of 1 mg/min over a period of at least 30 minutes to avoid the risk of
infusion-associated reactions. This reaction is thought to be related to
the lipid component of liposomal doxorubicin. In the event of such
a reaction with flushing, dyspnea, or facial swelling, the infusion
should be stopped immediately. If symptoms are minor, can restart
infusion at 50% the initial rate. Patients should not be rechallenged
in the face of a severe hypersensitivity reaction.
Careful monitoring is necessary to avoid extravasation. If extravasation
is suspected, immediately stop infusion, withdraw fluid, elevate extremity,
and apply ice to involved site. May administer local steroids. In
severe cases, consult plastic surgeon.
Monitor cardiac function before (baseline) and periodically during
therapy with either MUGA radionuclide scan or echocardiogram to
assess LVEF. Risk of cardiotoxicity is higher in patients _70 years
of age, in patients with prior history of hypertension or pre-existing
heart disease, in patients previously treated with anthracyclines, or in
patients with prior radiation therapy to the chest.
Monitor weekly CBC while on therapy.
Patients should be cautioned about the risk of hand-foot syndrome.
Patients should be warned about the potential for red-orange discoloration
of urine for 1–2 days after drug administration.
Pregnancy category D. Breast-feeding should be avoided.
Toxicity 1
Myelosuppression. Dose-limiting toxicity with leukopenia more common
than thrombocytopenia or anemia. Nadir usually occurs at days 10–14, with
full recovery by day 21.
Toxicity 2
Nausea and vomiting. Usually mild, occurring in 20% of patients.
Toxicity 3
Mucositis and diarrhea. Common but not dose-limiting.
Toxicity 4
Cardiotoxicity. Acute form presents within the first 2–3 days as arrhythmias
and/or conduction abnormalities, EKG changes, pericarditis, and/or
myocarditis. Usually transient and mostly asymptomatic. Not dose-related.
Chronic form results in a dose-dependent dilated cardiomyopathy associated
with congestive heart failure.
Toxicity 5
Skin toxicity manifested as the hand-foot syndrome with skin rash, swelling,
erythema, pain, and/or desquamation. Usually mild with onset at 5–6
weeks after the start of treatment. May require subsequent dose reduction.
More commonly observed in ovarian cancer patients (37%) than in those
with Kaposi’s sarcoma (5%).
Toxicity 6
Hyperpigmentation of nails, skin rash, and urticaria. Radiation recall skin
reaction can occur at prior sites of irradiation.
Toxicity 7
Alopecia. Common but generally reversible within 3 months after termination
of treatment.
Toxicity 8
Infusion reaction with flushing, dyspnea, facial swelling, headache, back
pain, tightness in the chest and throat, and/or hypotension. Occurs in about
5%–10% of patients, usually with the first treatment. Upon stopping the
infusion, resolves within several hours to a day.
Toxicity 9
Red-orange discoloration of urine. Usually occurs within 1–2 days after
drug administration.