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Pharmacology of Liposomal Daunorubicin and Its Use in Kaposi's Sarcoma

Pharmacology of Liposomal Daunorubicin and Its Use in Kaposi's Sarcoma

ABSTRACT: In the early 1980s, we first began to see cases of Kaposi's sarcoma (KS) in patients with the lymphadenopathy now known to be associated with infection by the human immunodeficiency virus (HIV). During that period, we were still looking at strong combinations of chemotherapeutic drugs to combat this disease, based on experience in nonimmunosuppressed African patients. It rapidly became apparent, however, that we needed both better regimens and more efficient ways of targeting antineoplastic agents to tumors, because these older regimens were highly toxic. This is a common problem throughout oncology but is particularly troublesome in the treatment of patients with the acquired immunodeficiency syndrome (AIDS). [ONCOLOGY 10(Suppl):28-33, 1966]

Introduction

The two key elements to improving the efficacy of an antineoplastic
drug--assuming that the drug is active against tumor cells--are
to deliver the drug to the tumor and to prevent it from damaging
other tissues on the way. Encapsulating cytotoxic agents, such
as daunorubicin (Cerubidine) in liposomes appears to address both
problems and thus can markedly improve the therapeutic ratio.

Characteristics of Liposomal Daunorubicin

DaunoXome is a combination of the antineoplastic anthracycline
agent daunorubicin with a liposomal carrier system. This type
of phospholipid structure arranges itself into a bilayer that
becomes spheric when placed in an aqueous solution. Drugs in an
aqueous solution, such as daunorubicin, can be trapped in the
aqueous center of such a structure. The DaunoXome system (
Figure
1
) is a unilamellar liposome composed of two typical components
of cell membranes--cholesterol and the phospholipid distearoyl
phosphatidylcholine--in approximately a 1:2 ratio. This particular
lipid composition has been optimized to produce liposomes with
remarkable physical stability and a particularly high affinity
for solid tumors in vivo [1]. To maximize tumor targeting further,
the DaunoXome liposomes are filtered so the particles are within
the 35-nm-to-65-nm range; tumor blood vessels have increased permeability
to particles in this range. Another important benefit of this
formulation is that it can be used concurrently with the more
commonly prescribed antiretrovival agents without increased risk.

Pharmacokinetics of Free vs Liposomal
Daunorubicin

A comparison of the plasma levels of daunorubicin in patients
administered similar doses of daunorubicin in either conventional
or liposomal formulations demonstrated that peak plasma levels
of DaunoXome are 100-fold higher than those for free daunorubicin
(
Figure 2) [2]. The mean area under the curve (AUC) for plasma
concentrations of daunorubicin is 36-fold higher with DaunoXome
than with free daunorubicin. This appears to be due to the fact
that free daunorubicin is rapidly eliminated, whereas plasma levels
of daunorubicin in patients administered DaunoXome remain high
for many hours. The retention of daunorubicin within circulating
liposomes has been confirmed by studies in which the lipid and
aqueous components of the liposomes were radiolabeled separately.
These studies revealed that these structures are stable to leakage
for at least 30 hours in the circulation. Because free daunorubicin
fluoresces, quenching this fluorescence can be used to monitor
the retention of daunorubicin by liposomes. Fluorescence-quenching
experiments demonstrated that more than 95% of daunorubicin remains
associated with liposome for at least 12 hours in the circulation.

The pharmacokinetics of free daunorubicin vs liposome-encapsulated
daunorubicin have also been studied in CD2F1 mice bearing P-1798
lymphosarcomas [3]. Both drugs were given intravenously at 20
mg/kg. At 1 hour following administration, the plasma level of
free daunorubicin was 1.4 mg/mL, whereas the plasma level of daunorubicin
was 268 mg/mL after administration of DaunoXome. The ratios of
the AUC of free drug relative to DaunoXome were most significantly
increased (10-fold) in tumor tissue. Similarly, in DaunoXome-treated
mice, the peak tumor level of daunorubicin was 100 mg/g, which
occurred approximately 8 hours following administration; in free
daunorubicin-treated mice, the peak tumor level of daunorubicin
was 9.6 mg/g and occurred 1 hour after administration.

Tumor Targeting of Liposomal Drugs

Although the specific mechanism by which DaunoXome is preferentially
delivered to solid tumors in situ has not been established, a
dramatically higher level of daunorubicin is achieved in tumors
with DaunoXome than after treatment with free daunorubicin [4].Laser-induced
fluorescent video imaging has shown that as liposomes break down,
daunorubicin is released only within the tumor mass, not in the
surrounding normal tissue [5]. Autoradiography has shown a specific
and dramatic targeting of KS lesions with indium-111-labeled liposomes
[6]. Experimental studies of mice bearing J6456 lymphoma cell
tumors revealed that liposomal formulations of gallium-67-labeled
deferoxamine, containing monosialoganglioside, cholesterol, and
distearoyl phosphatidylcholine, were retained in the blood and
accumulated in tumors at markedly higher levels than were liposomes
composed of other constituents [7].

Therapeutic Efficacy of Free vs Liposomal
Daunorubicin

Given that this type of carrier brings the anticancer drug to
the tumor, what evidence is there that this has any therapeutic
importance? Mouse MA16C mammary adenocarcinoma cells were implanted
subcutaneously into mice and were used as a model system for testing
the antitumor efficacy of liposomal daunorubicin [3]. Four days
after implantation, single intravenous doses of free daunorubicin
(2 to 40 mg/kg) or DaunoXome (2 to 50 mg/kg) were given. (The
higher DaunoXome maximum dose was possible because of reduced
toxicity; see below.)

The median time of survival was 36 days for untreated control
mice bearing MA16C tumors, 70 days for mice treated with 20 to
25 mg/kg doses of free daunorubicin, and 114 days for mice treated
with 15 to 35 mg/kg of DaunoXome. In the free daunorubicin groups,
there were 4 long-term survivors of a total of 90, as opposed
to 40 survivors of 80 in the DaunoXome groups. Furthermore, treatment
with the most effective dose of DaunoXome (25 mg/kg) cured all
10 mice treated with this concentration of drug. All were long-term
survivors, with no gross evidence of tumor. In contrast, the most
effective dose of free daunorubicin (20 mg/kg) cured only 4 of
10 treated mice. Of the 80 mice treated with DaunoXome, 15 had
complete regression of subcutaneous tumors, which was later confirmed
at necropsy. The increased survival observed with DaunoXome treatment
in murine solid tumor models indicates that the strategy of enclosing
daunorubicin in this type of liposome effectively increases the
cytotoxicity for the malignant cells.

Toxicity Profiles

Phase I and II clinical trial experiences with patients with KS
have demonstrated that, in general, DaunoXome is associated with
fewer side effects than free daunorubicin [8,9]. The primary toxicity
is myelosuppression, which is much milder than that observed with
conventional anthracyclines; this is perhaps due to the decrease
in free drug in the circulation. Cardiotoxicity has not been observed,
despite cumulative doses of more than 1,000 mg in several patients.
The latter finding is supported by data from mouse toxicology
studies that showed little accumulation of liposome-encapsulated
daunorubicin in cardiac tissues [10]. Alopecia and tissue necrosis
associated with drug extravasation at the injection site have
not occurred. Other complications, including nausea, vomiting,
and mucositis, occurred infrequently. These studies demonstrated
a significant improvement in the therapeutic ratio for the liposomal
formulation DaunoXome, and clinical experience has confirmed that
this is an effective drug for use in the treatment of KS in patients
with AIDS [8,9].

Current Studies of the Use of Liposomal
Daunorubicin for Kaposi's Sarcoma

AIDS-related KS often presents as cutaneous disease with nodular
lesions that may rapidly progress. Up to 50% of patients have
oral cavity or gastrointestinal tract involvement, which may lead
to abdominal pain, early satiety, or gastrointestinal hemorrhage.
Pulmonary involvement is a common, serious problem. Even in cases
in which KS is not life-threatening, extensive cutaneous disease
can cause significant morbidity. Patients may become disfigured
and are subject to skin ulceration, bleeding, and edema at a time
when they are already dealing with the psychological implications
of AIDS [11,12].

Therapeutic options for KS in these patients are limited. Interferon-a
is the only agent approved specifically for this indication; this
agent only benefits the minority of patients with CD4 cell counts
higher than 400/mm³. Furthermore, even in cases where interferon-a
is efficacious, there are frequently problems with drug toxicity;
patients ultimately develop progressive disease despite continued
treatment [13]. For these patients, as well as for those deemed
unlikely to respond to interferon-a, chemotherapy is generally
used. Chemotherapy often makes use of either single agents (such
as bleomycin [Blenoxane], vincristine [Oncovin], vinblastine [Velban],
doxorubicin [Adriamycin], or etoposide [VePesid] or combinations
(such as Adriamycin, bleomycin, and vincristine [ABV]). Although
significant response rates have been reported with the ABV combination,
toxicities often limit the duration of treatment [14].

In this setting, it was considered worthwhile to evaluate DaunoXome
for the management of AIDS-related KS. This approach was chosen
for several reasons: the proven antitumor efficacy of conventional
daunorubicin, the ability of the liposomal daunorubicin formulation
to be targeted to KS lesions [6], and preclinical studies suggesting
that the liposomal form was likely to cause fewer side effects
than conventional daunorubicin or ABV. Toxic effects with ABV
include cardiotoxicity from doxorubicin, pulmonary toxicity from
bleomycin, and neurotoxicity from the vinca alkaloids. All these
drugs may increase the risk of infectious complications and gastrointestinal
toxicity seen with each treatment cycle; this can be particularly
hazardous for an immunocompromised population of patients [15].

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