Note: Descriptions are shown in the official language in which they were submitted.
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METHOD AND COMPOSITIONS FOR ADMINISTERING
TAXANES ORALLY TO HUMAN PATIENTS
FIELD OF THE INVENTION
The invention relates to methods and compositions
for orally administering to humans pharmaceutical agents that
are poorly absorbed from the gastrointestinal tract, and to
methods of treatment of patients through the oral
administration of such agents. More particularly, the present
invention relates to methods and compositions for orally
administering paclitaxel and related taxanes to humans.
BACKGROUND OF THE INVENTION
Many valuable pharmacologically active compounds
cannot be effectively administered by the oral route to human
patients because of poor or inconsistent systemic absorption
from the gastrointestinal tract. All these pharmaceutical
agents are, therefore, generally administered via intravenous
routes, requiring intervention by a physician or other health
care professional, entailing considerable discomfort and
potential local trauma to the patient and even requiring
administration in a hospital setting with surgical access in
the case of certain intravenous (i.v.) infusions.
One of the important classes of cytotoxic agents
which are not normally bioavailable when administered orally
to humans are the taxanes, which include paclitaxel, its
derivatives and analogs. Paclitaxel (currently marketed as
TAXOL'~ by Bristol-Meyers Squibb Oncology Division) is a
natural diterpene product isolated from the pacific yew tree
(Taxus brevifolia). It is a member of the taxane family of
terpenes. It was first isolated in 1971 by Wani et al., (J.
Am. Chem. Soc., 9.3:2325, 1971), who characterized its
structure by chemical and X-ray crystallographic methods. One
mechanism for its activity relates to the capacity of
paclitaxel to bind tubulin, thereby inhibiting cancer cell
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growth. Schiff et al., Proc. Natl. Acad. Sci. USA, 77:1561-
1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kuman,
J. Biol. Chem., 256:10435-10441 (1981).
Paclitaxel has been approved for clinical use in the
treatment of refractory ovarian cancer in the United States
(Markman et al., Yale Journal of Biology and Medicine, 64:
583, 1991; McGuire et al., Ann. Intern. Med., 111:273, 1989).
It is effective for chemotherapy for several types of
neoplasms including breast (Holmes et al., J. Nat. Cancer
Inst., 83:1797, 1991) and has been approved for treatment of
breast cancer as well. It is a potential candidate for
treatment of neoplasms in the skin, lung cancer and head and
neck carcinomas (Forastire et al., Sem. Oncol., 20:56, 1990).
The compound also shows potential for the treatment of
polycystic kidney disease (Woo et al., Nature, 368:750, 1994)
and malaria.
The poor solubility of paclitaxel in water has
created significant problems in developing suitable injectable
and infusion formulations useful for anticancer chemotherapy.
To improve the solubility of paclitaxel in aqueous solutions,
some paclitaxel compositions formulated for IV infusion have
included CREMOPHOR~ EL (a condensation product of
polyethoxylated castor oil and ethylene oxide sold by BASF).
For example, paclitaxel used in clinical testing under the
aegis of the National Cancer Institute (NCI) has been
formulated in 50o CREMOPHOR~ EL and 50a dehydrated alcohol.
CREMOPHOR~ EL has proven to be toxic and to produce
vasodilation, labored breathing, lethargy, hypotension and
death in dogs following IV administration. It is also believed
to cause allergic-type or hypersensitivity reactions.
Evidence also exists that paclitaxel itself provokes acute
hypersensitivity reactions in the absence of CREMOPHOR~EL.
Paclitaxel analogs derivatized at the 2' and/or 7-
positions with groups that enhance water solubility have been
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synthesized. These efforts have yielded prodrug compounds
that are more water soluble than the parent compound and that
display the cytotoxic properties upon activation. One
important group of such prodrugs includes the 2'-onium salts
of paclitaxei and docetaxel, particularly the 2'-
methylpyridinium mesylate (2'-MPM) salts.
Animal studies have demonstrated that paclitaxel is
very poorly absorbed when administered orally (less than 1%).
See Eiseman, °t al., Second NCI Workshop on Taxol and Taxus
(Sept. 1992); Suffness et al., in Taxol Science and
Applications (CRC Press 1995). Eiseman, et al., indicate that
paclitaxel has a bioavailability of 0% upon oral
administration, and Suffness, et al., report that oral dosing
with paclitaxel did not seem possible because no evidence of
antitumor activity was found on oral administration up to 160
mg/. kg/ day .
In PCT application WO 95/20980 (published August 10,
1995), Benet, et al., disclose a purported method for
increasing the bioavailability of orally administered
hydrophobic pharmaceutical compounds. This method comprises
orally administering such compounds to the patient
concurrently with a bioenhancer comprising an inhibitor of a
cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein-
mediated membrane transport. Benet, et al., however, provide
virtually no means of identifying which bioavailability
enhancing agents will improve the availability of specific
"target" pharmaceutical compounds, nor does it indicate
specific dosage amounts, schedules or regimens for
administration of the enhancing or target agents. Benet lists
dozens of potential enhancers (P450 3A inhibitors) and target
drugs (P450 3A substrates) but the only combination of
enhancer and target agent exemplified in terms of experimental
evidence is ketoconazole as the enhancer and cyclosporin A as
the target drug.
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Thus, a need remains for methods of administering
taxanes, e.g., paclitaxel which are cytotoxic compounds, that
are safe and effective, and particularly methods that reduce
adverse reactions associated with parenteral administration of
paclitaxel and various solubilizers and excipients such as
CREMOPHOR~ EL.
SUMMARY OF THE INVENTION
One aspect of the present invention is directed to a
method of reducing incidence or severity of hypersensitivity
reactions associated with parenteral administration of a
taxane. The method entails orally administering a taxane
formulation wherein the formulation causes hypersensitivity
reactions when administered parenterally. In preferred
embodiments, the taxane is selected from the group of
paclitaxel, docetaxel, a derivative, analog, or prodrug of
paclitaxel or docetaxel e.g., paclitaxel-2'MPM and docetaxel-
2'-MPM, taxane 2'MPM salts and polymorphs and hydrates
thereof. It is preferred that the taxane is present in the
formulation in an amount from about 60 mg/mz to about 250
mg/m2 .
Applicants have also discovered that the gut is
substantially impervious to orally administered CREMOPHOR~ EL.
That is, cremophor is not transported across the gut epithelia
to achieve detectable levels in blood. Accordingly, another
aspect of the present invention is directed to a method of
selectively enhancing the bioavailability of a
pharmaceutically active agent. The method involves orally co-
administering to a human a bioavailability enhancing agent and
a formulation including a pharmaceutically active agent and at
least one solvent. Preferred bioavailability enhancing agents
include cyclosporins A-Z, dihydrocyclosporin A,
dihydrocyclosporin C, acetyl cyclosporin A, PSC-833 and SDZ-
NIM 811. The pharmaceutical agent achieves therapeutic blood
levels but the solvent that tends to cause the adverse side
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reactions such as hypersensitivity does not achieve active
blood levels. In preferred embodiments, the pharmaceutical
agent is a taxane and the solvent is a polyalkoxylated castor
oil such as CREMOPHOR'~ EL. In more preferred embodiments, the
CREMOPHOR is present in the formulation in an amount from
about 3 to about 10 mg/ml.
A further aspect of the present invention is
directed to a composition containing a taxane and a
polyaikoxylated castor oil (optimally including an excipient)
in the form of an oral dosage unit.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph reflecting the circulating levels
of paclitaxel in samples taken: (a) lower curve - over a
period of 6-8 hours from one group of rats administered only
oral paclitaxel, and (b) upper curve - over a period of 24
hours from a second group of rats administered orally one hour
prior to the co-administration of oral cyclosporin A and oral
paclitaxel.
FIG. 2 is a graph reflecting the levels of
paclitaxel in plasma samples from a human patient administered
oral paclitaxel after two dose of oral cyclosporin A, the
first administered one hour before the paclitaxel dose and the
second administered immediately before the paclitaxel.
FIG. 3 is a graph reflecting the levels of
paclitaxel in plasma samples from a second human patient
administered oral paclitaxel by the same regimen as described
with respect to FIG. 2.
FIG. 4 is a graph reflecting a comparison of the
paclitaxel plasma level curves determined over 24 hours in
rats (FIG. 1) and in humans (FIGS. 2 ~.nd 3) administered oral
paclitaxel after two doses of oral cyciosporin A.
FIG. 5 is a table reflecting treatment schedule of
oral paclitaxel and cyclosporin used in Example 5.
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FIG.6 is a table reflecting the hematologic toxicity
after oral administration of paclitaxel described in Example
FIGS.7A and 7B are tables reflecting the non-
hematologic toxicity after oral administration of paclitaxel
described in Example 5.
FIG.8 is a table reflecting the pharmacokinetics of
oral paclitaxel described in Example 5.
FIG.9 is a table reflecting the pharmacokinetics of
CsA described in Example 5.
FIG. I0 is a graph reflecting the area under the
curve (AUC, (uM.h)) of oral paclitaxel versus dose (mg/m').
DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the present invention provides a method
of preventing or reducing hypersensitivity and allergic
reactions in human patients receiving taxane therapy. The
method comprises the oral administration of the taxane to the
patients. Oral administration by the instantly disclosed
method is much less likely than intravenous therapy to produce
such adverse reactions. Applicants administered paclitaxel to
human patients (see Examples 2 and 3) with no pre-medication
(e. g., no H-1 H-2 blockers or steroids). Therapeutic
circulating levels of paclitaxel were achieved and no
hypersensitivity reactions were observed.
Applicants have discovered that the taxanes, which
have been believed to be characterized by therapeutically
inadequate oral absorption profiles, can be administered
orally to humans with sufficient systemic absorption and oral
bioavailability achieved to exhibit plasma levels in the
therapeutic range. The term '~bioavailability" as used herein
refers to the systemic availability (i.e., blood/plasma
levels) of a given amount of drug administered to a patient.
Applicants have actually administered the taxane paclitaxel
orally to human patients suffering from cancers and have
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verified that therapeutic blood levels of paclitaxel were
achieved ir~ these patients over extended periods of time.
In a preferred embodiment, the taxane is co-
administered with an absorption or bioavailability enhancing
agent to a human patient. "Co-administration" of the
enhancing agent comprehends administration substantially
simultaneously with the taxane (either less than 0.5 hr.
before, less than 0.5 hr. after or together) , from about 0.5
to about 72 hr. before the administration of the taxane, or
both, i.e., with one or more doses of the same or different
enhancing agents given at least 0.5 hr. before and one dose
given substantially simultaneously with (either together with
or immediately before or after) the taxane. Additionally,
"co-administration" comprehends administering more than one
dose cf taxane within 72 hr. after a dose of enhancing agent,
in other words, the enhancing agents) need not be
administered again before or with every administration of
taxane but may be administered intermittently during the
course of treatment.
The orally administered enhancing agents useful in
practicing the preferred embodiment of the invention include,
but are not limited to cyclosporins, including cyclosporins A
through Z but particularly cyclosporin A (cyclosporin),
cyclosporin F, cyclosporin D, dihydro cyclosporin A, dihydro
cyclosporin C, acetyl cyclosporin A, PSC-833, and SDZ-NIM 811
i.e., ((Me-lle-4)-cyclosporin, an antiviral, non-
immunosuppressive cyclosporin)(both available from Novartis
Pharmaceutical Corp). The structures of cyclosporins A-Z are
described in Table 1 below.
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TABLE 1
Cyclosporins A-Z
==== Aminoacids
I
Cy- _ 2 3 4 S 6 7 B 9 10 11
CyA Mebmt Abu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVai
CyB Mebmt Ala Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyC Mebmt Thr Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyD Mebmt Val Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyE Mebmt Abu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu Val
CyF DesoxyAbu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
Mebmt
CyG ~ Mebmt Nva Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
~
CyH Mebmt Abu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyI Mebmt Val Sar MeieuVai MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyK DesoxyVal Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
Mebmt
CyL Bmt Abu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyM Mebmt Nva Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyN Mebmt Nva Sar MeLeuVal MeLeu Ala D-Ala MeLeuLeu MeVal
Cy0 MeLeu Nva Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyP Bmt Thr Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyQ Mebmt Abu Sar Val Val MeLeu Ala D-Ala MeLeuMeLeu MeVal
CyR Mebmt Abu Sar MeLeuVal Leu Ala D-A1a MeLeuLeu MeVal
-
CyS Mebmt Thr Sar Val Val MLeu Ala D-Ala MeLeuMeLeu MeVa1
Cy'T Mebmt Abu Sar MeLeuVal Meleu Ala D-Ala MeleuLeu MeVal
CyU Mebmt Abu Sar MeLeuVal Leu Ala D-Ala MeLeuMeLeu MeVal
CyV Mebmt Abu Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu MeVai
~
CyW Mebmt Thr Sar MeLeuVal MeLeu Ala D-Ala MeLeuMeLeu Val
~
CyX Mebmt Nva Sar MeLeuVal MeLeu Ala D-Ala Leu MeLeu MeVal
CyY Mebmt Nva Sar MeLeuVal MeLeu Ala D-Ala Leu MeLeu MeVal
CyZ Me Abu Sar MeLeuVal MeLeu Ala D-A1a MeLeuMeLeu MeVal
Amino
octyl
acid
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Cyclosporins are neutral, lipophilic, cyclic
undecapeptides with molecular weights of about 1200, and that
exhibit immunosuppressive properties. They are produced by
the members of the genus Topycladium, including e.g.,
Topycladium inflatum Gams (formerly designated as Trichoderma
polysporum), Topycladium terricola and other fungi imperfecti.
The major component is cyclosporin A, also referred to as
cyclosporine or CsA. several other lesser metabolites,
including cyclosporins B through Z, have been found to exhibit
substantially less immunosuppressive activity than cyclosporin
A, or in some cases, no immunosuppressive activity. They are
used intravenously or orally as immunosuppressants, primarily
for organ transplantation and certain other conditions.
Cyclosporins, particularly cyclosporin A, are known inhibitors
of the P-glycoprotein efflux pump and other transporter pumps
as well as of certain cytochrome P450 degradative enzymes, but
to date no effective regimens for applying this property
clinically have been developed to the point of clinical and
commercial feasibility or regulatory approval. A number of
synthetic and semi-synthetic analogs have been prepared. See
generally Jegorov, et al., Phytochemistry 38:403-407 (1995).
Natural, semi-synthetic and synthetic analogs of cyclosporins
may be used in the practice of the present invention.
The cyclosporin may be chosen without regard as to
whether it exhibits immunosuppressive activity in vivo. One
of the surprising discoveries of the invention is that the
immunosuppression observed with certain cyclosporins is not
inextricably linked to improvement in oral bioavailability of
therapeutic agents. Thus, cyclosporin F enhances the oral
bioavailability of paclitaxel even though it has been reported
not to display immunosuppresive activity. Stewart, et al.,
Transplantation Proceedings 20(Supp. 3):989-992 (1998);
Granelli-Piperno, et al., Transplantation 46: 53S-60S (1988).
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Without intending to be bound by any particular
theory of operation, a possible explanation for the observed
increased bioavailability of paclitaxel is that there is
interaction at the level of the drug metabolizing enzymes for
cyclosporine and paclitaxel. It is known that both agents are
highly metabolized by the cytochrome P-450 system (e.g., P-450
3A) , which is concentrated in the liver as well as the small
intestine. It is conceivable that cyclosporine administered
prior to the taxane inhibits these enzymes so that paclitaxel,
which is non-polar and lipophilic, is absorbed. In the
absence of this local inhibition, paclitaxel is metabolized to
more polar metabolites that do not transverse the mucosa.
This theorized inhibition of gut metabolism of the
target agent might have little or no effect in increasing
systemic blood levels when the target agent is administered
intravenously. Moreover, since the primary effect of the oral
absorption-enhancing agent may be a local effect in the gut
lumen, doses which are sub-therapeutic (e.g., in terms of
immunosuppression) should be effective in achieving the
desired effect. This is an important consideration in the
case of enhancing agents such as cyclosporins that have
powerful immunosuppressive activity and can present toxicity
problems if administered at high dose levels. Thus,
Applicants' observation that non-immunosuppressive
cyclosporins, such as cyclosporin F, can still function as an
oral enhancer is of great clinical value.
The term "taxane" includes but is not limited to
paclitaxel, paclitaxel analogs such as docetaxel (N-debenzoyl-
N-tert-butoxycarbonyl-10-deacetyl paclitaxel), derivatives,
analogs and prodrugs of paclitaxel and docetaxel e.g., salts
such as paclitaxel-2' methylpyridinium (MPM) and docetaxel-2'-
MPM, taxane 2'MPM salts, and polymorphs and hydrates thereof.
The dosage range of orally administered taxane target agents
will vary from compound to compound based on its therapeutic
index, the requirements of the condition being treated, the
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status of the patient and so forth. The method of the
invention makes it possible to administer paclitaxel and other
taxanes orally ranging from about 20 mg/m' to about 1000 mg/m'
(based on patient body surface area) or about 2-30 mg/kg
(based on patient body weight) as single or divided (2-4)
daily doses, and maintain the plasma levels of paclitaxel in
humans in the range of 50-500 ng/ml for extended periods of
time (e. g., 8-12 hours) after each oral dose. These levels
are at least comparable to those achieved with 96-hour IV
infusion taxol therapy (which causes the patient great
inconvenience, discomfort, loss of quality time, infection
potential, etc.). Moreover, such plasma levels of paclitaxel
are more than sufficient to provide the desired
pharmacological activities of the target drug, e.g.,
inhibition of tubulin disassembly (which occurs at levels of
abut 0.1 ~.M, or about 85 ng/ml) and inhibition of protein
isoprenylation (which occurs at levels of about 0.03 ~,M, or
about 25 ng/ml) which are directly related to its antitumor
effects by inhibiting oncogene functions and other signal-
transducing proteins that play a pivotal role in cell growth
regulation. The tumor does not distinguish how the anti-
cancer drug was administered.
Preferred oral dosage amounts for paclitaxel and
other taxanes administered according to the invention are
about 60-250mg/m2 or about 2-6 mg/kg. It may be suitable in
some instances to administer to the patient a higher initial
loading dose of the target agent to achieve peak blood levels,
followed by lower maintenance doses.
The dosage range of the enhancing agent co-
administered with the taxane in accordance with the invention
is about 0.1 to about 20 mg/kg of patient body weight. Two or
more different enhancing agents and/or two or more different
target agents may be administered together, alternately or
intermittently in all of the various aspects of the method of
the invention.
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The present invention may be employed to treat human
par.ients afflicted with cancers, tumors, Kaposi's sarcoma,
malignancies, uncontrolled tissue or cellular proliferation
secondary to tissue injury, and any other disease conditions
respor_sive to taxanes. Among the types of carcinoma that may
be treated particularly effectively are hepatocellular
carcinoma and liver metastases, cancers of the
gastrointestinal tract, pancreas, prostate and lung, and
Kaposi's sarcoma. Examples of non-cancerous disease
conditions which may be effectively treated with these active
agents administered orally in accordance with the present
invention are uncontrolled tissue or cellular proliferation
secondary to tissue injury, polycystic kidney disease,
inflammatory diseases (e. g., arthritis) and malaria, including
choroquine- and pyrimethamine-resistant malaria parasites.
See, Pouvelle, et al., J. Clin. Invest. 44:413-417 (1994).
The invention is particularly useful in the
treatment of patients with primary tumors and metastases. The
active ingredient penetrates the gut wall as a result of the
co-administration of the cyclosporin enhancer and is taken up
by the portal circulation rapidly, providing a higher local
initial concentration of the chemotherapeutic agent in the
liver. This local concentration may in fact be higher than
the concentration currently achieved with IV infusion
therapy). Higher levels of paclitaxel in the liver after oral
administration may not be reflected in increased plasma levels
because of the high first pass effect of the liver. The
method of the invention, in selectively producing high, blood
concentrations of antitumor agents, is particularly valuable
in the treatment of liver cancers (e. g., hepatocellular
carcinoma and liver metastases), gastrointestinal cancers
(e. g., colon, rectal) and lung cancers.
It is emphasized that this aspect of the present
invention does not require any particular bioavailability
enhancing agent. Nor is it restricted to any specific dosage
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amounts or regimens. In less preferred embodiments, the
taxane is administered without a bioavailability enhancing
agent.
Another aspect of the present invention is directed
to a composition containing a taxane in the form of an oral
dosage unit. The dosage unit may be in the form of
conventional tablets, capsules (soft gel or hard gel),
caplets, gel caps, pills, liquids (e. g., solutions,
suspensions or elixirs), powders, lozenges, micronized
particles or osmotic delivery systems and any other oral
dosage forms known in the pharmaceutical arts. In preferred
embodiments, the dosage unit is in the form of a liquid and
includes paclitaxel or other taxane in a vehicle comprising
CREMOPHOR~ EL or other polyalkoxylated castor oil (e.g., a
polyethoxylated castor oil), alcohol and/or a polyoxyethylated
sorbitan mono-oleate (e. g., TWEEN 80, ICI Americas, Inc.),
transcutol and optionally a flavorant. Each dosage unit
includes an effective amount of a taxane and a carrier. The
carrier may contain one or more of the following ingredients,
namely vehicles, fillers, binders or excipients,
disintegrants, solvents, sweeteners, coloring agents and any
other inert ingredients which are regularly included in
pharmaceutical dosage forms for oral administration. See,
Remington's Pharmaceutical Sciences, 17th edition (1985).
Precise amounts of each of the taxane in the oral
dosage forms will vary depending on the age, weight, disease
and condition of the patient. For example, paclitaxel or
other taxane dosage forms may contain sufficient quantities of
the target agent to provide a daily dosage of about 20-1000
mg/m' (based on patient body surface area) or about 2-30
mg/kg. mg/kg (based on patient body weight) as single or
divided (2-3) daily doses. Preferred dosage amounts are about
50-200 mg/m2 or about 2-6 mg/kg.
Dosing schedules will also vary depending on factors
such as the patient's characteristics and disease status.
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Preferred dosing schedules for administration of oral
paclitaxel are (a) the daily administration to a patient in
need thereof of 1-4 equally divided doses providing about 20-
1000 mg/m' (based on body surface area), and preferably about
JO-200 mg/m', with the daily administration being continued
for 1-4 consecutive days each 2-3 weeks, or (b) administration
for about one day each week. The former schedule is
comparable to use of a 96-hour paclitaxel infusion every 2-3
weeks, which is considered by some a preferred IV treatment
regimen.
Oral administration of taxanes in accordance with
the invention actually decreases toxic side effects in many
cases as compared with currently utilized IV therapies.
Without intending to be bound by theory, Applicants believe
that as opposed to IV infusion which produces a sudden and
rapid high concentration in blood levels, oral administration
results in absorption of the active agent through the gut wall
(promoted by the enhancing agents), a more gradual appearance
in the blood levels and a stable, steady-state maintenance of
those levels at or close to the ideal range for a long period
of time .
The plasma levels of the taxanes administered in
accordance with preferred embodiments of the present invention
are remarkably and surprisingly similar to the levels observed
following IV administration. A series of studies with
experimental animals showed that steady state plasma levels of
paclitaxel were achieved upon oral co-administration with CsA
by the third day of the regimen. The levels of the target
agent achieved at steady state were comparable to those
achieved in patients by a 96-hour IV infusion of paclitaxel.
A 27o response rate was found in patients with metastatic
breast cancer treated with a continuous 96-hour infusion every
three weeks (Siedman et al., J. Clin Oncol., 14:1877, 1996)
who had previously failed 3-hour infusions of taxane (taxol or
taxotene). Comparable blood level results can be achieved with
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the treatment methods of the present invention without the
discomfort, inconvenience and risks of prolonged IV infusions.
The data reflected in FIGS. 1-4 are especially
noteworthy in view of the surprising nature of the results.
As described in more detail in the Examples set forth below,
the data reflected in FIG. 1 were generated from studies of
paclitaxel administration to rats, but the data reflected in
FIGS. 2 and 3 reflect actual concentration levels of
paclitaxel over time in the plasma of two human patients
administered oral paclitaxel in accordance with the present
invention, i.e., with co-administration of an oral cyclosporin
enhancing agent. The human data are remarkable not merely
because they reflect for the first time, to the extent found
in the literature, that paclitaxel was administered orally to
human beings requiring paclitaxel therapy, but also because
therapeutic-level plasma concentrations were achieved and
maintained over about a 10-hour period; indeed, the level of
drug seen in the plasma of the human patients were comparable
to the levels achieved upon IV administration and the methods
used did not bring about serious local or systemic side
effects. Furthermore, it should be noted that plasma levels
are a reflection of the concentration of paclitaxel in tissue.
It has now been demonstrated that the rat
pharmacokinetic profile of paclitaxel co-administered with
oral cyclosporin A is quite comparable to the profile in human
patients receiving the same regimen. Indeed, FIG. 4 reflects
a superimposition on the same graph of the plasma
concentration curves for paclitaxel over a 24-hour period
following oral co-administration of two doses of enhancer
(cyclosporin A) spaced on hour apart with oral paclitaxel
administered after the second dose of enhancer (cyclosporin A)
spaced one hour apart with oral paclitaxel administered after
the second dose of enhancer, said data being derived from the
24-hour rat study reflected in-FIG. 1 and the studies on human
patients reflected in FIGS 2 and 3. It may be observed that
the three curves on the graph in FIG. 4 (one rat and two
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human) are cf very similar configuration, indicating that the
results ir~ human are consistent with the animal test results.
The rat is an accepted model for assessing the
pharmacokinetics and absorption profiles of chemotherapeutic
agents. It. is equally well established, however, that results
in animals are not predictive of results in humans due to
known species-to-species variations. Thus, no clinician or
medical practitioner would have administered paclitaxel or
other taxanes orally to humans with reasonable confidence
based on the animal data alone without any human clinical
experience. Furthermore, doctors are unlikely to experiment
with drugs in life-threatening conditions, i.e., cancer, when
data are unavailable. The present invention, therefore,
teaches a method whereby taxanes can be orally administered
safely and effectively to humans. From the standpoint of a
physician, the current invention is a vast improvement over
the prior art because it allows for the utilization of the
beneficial properties of a taxane such as paclitaxel without
the necessity of intravenous catheters and time spent in a
hospital or chemotherapy clinic, as well as the availability
of a clinic and the attendant expense, inconvenience and risk
of infection to the patient, pre-medication to avoid
hypersensitivity or allergic reactions, and potential adverse
effects from the pre-medications themselves.
Paclitaxel use is associated with a variety of
toxicities and side effects. Two of the most noteworthy
toxicities are neutropenia and neuropathy. A variety of
clinical data have shown that it would be desirable to keep
the circulating plasma concentrations within a certain
"window" in order to maximize the anti-tumor activity and
minimize the side effects, especially neutropenia. For many
tumor types, it is believed that low, but long-term exposure
of tumor cells in the body results in better clinical results.
Thus, plasma levels of about .03 micromolar would be expected
to block cell division. There are clinical data showing that
constant intravenous administration over several days to
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achieve a "window" of about 0.05 to 0.1 micromolar in the
circulatier~ can minimize toxicities and cause tumor
regressions, sometimes even in patients whose tumors did not
respond to 3-hour infusion regimens. The currently approved
3-hour infusion regimens of paclitaxel achieve peak plasma
concentrations that greatly exceed these levels.
The present invention makes it possible to give
paclitaxel in comparatively infrequent daily doses (e. g.,
about twice/day) according to schedules that would otherwise
not be possible or practical with the intravenous route. The
use of the enhancer (e. g., cyclosporin A) promotes oral
absorption of paclitaxel for the first dose and if a second
paclitaxel dose is to be given later in the day,.the use of
additional cyclosporin A may not even be needed. Thus,
paclitaxel can be given intermittently as single dose on a
fixed schedule (weekly, biweekly, etc.) or chronically, over a
period of consecutive days (e. g., 4 days) every 2-4 weeks with
the goal of keeping the levels within the safe and effective
"window" and reducing the toxicities discussed above.
Another aspect of the invention is directed to a
method of selectively enhancing the bioavailability of a
taxane or other pharmaceutical agent. The method entails
orally co-administering to a patient a bioavailability
enhancing agent and a formulation containing the
pharmaceutical agent and a solvent. The pharmaceutical agent
achieves therapeutic blood levels but the solvent is not
absorbed. Because of its physico-chemical properties,
paclitaxel has been typically dissolved in Cremophor for IV
administration. The speculation has been that Cremophor is
responsible for some of the allergic-type reactions
experienced by patients receiving paclitaxel therapy. As a
result, patients are pre-medicated to avoid or reduce
hypersensitivity reactions. Paclitaxel must be given slowly
to patients, with medical personnel in a state of constant
vigilance for severe hypersensitivity reactions. For standard
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intravenous regimens, pre-medication regimens of H-i and H-2
blockers plus steroids are generally required.
Applicants have discovered that oral co-
administration of a bioavailability enhancing agent and a
taxane formulation containing the taxane, CREMOPHOR'~ EL and
ethanol results in uptake of the taxane tc achieve
pharmacologically effective or therapeutic blood levels with
no appreciable blood level of the Cremophor so as to cause
adverse side effects. Accordingly, this aspect of the present
invention embraces the use of any pharmaceutical agent that is
soluble in a solvent such as a.polyalkoxylated castor oil that
tends to cause adverse side effects such as hypersensitivity
reactions when administered parenterally. The enhancing agent
facilitates uptake or absorption of the pharmaceutically
active agent through the gut but it does not exert this action
with respect to the solvent.
Taxanes are preferred active agents. Other agents
include antineoplastic drugs such as chemotherapeutic agents
(e. g., etoposide, camptothecin, CPT-11 (Pharmacia/UpJohn),-
doxorubicin, vincristine, davnorubicin, mitoxanthrone and
colchicine'J, and ganciciovir and foscarnet. In preferred
embodiments, fixed quantities of the bioavailability enhancing
agent and the pharmaceutically active agent are formulated
together in a combination oral dosage form. Such dosage forms
can consist of tablets, capsules, caplets, gel caps, pills,
liquids or lozenges. One such combination product includes
from about 0.1 to about 20 mg/kg of one or more of
cyclosporins A, D, C, F and G, dihydro CsA, dihydro CsC and
acetyl CsA together with about 20 to about 1000 mg/m2 (based
on average patient body surface area), and preferably about
50-200 mg/m2, of paclitaxel, docetaxel, other taxanes or
paclitaxel or docetaxel derivatives such as paclitaxel 2'-MPM
or docetaxel 2'-MPM.
In other preferred embodiments, the solvent contains
a polyalkoxylated castor oil such as CREMOPHOR~ EL in an
amount of from about 3 mg/ml to about 10 mg/ml.
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In the case of the pharmaceutically active agents
that exhibit anti-neoplastic activity, the co-administration
of enhancing agent enhances activity at sites highly protected
by MDR e.g., the testes and the brain. Thus, the present
invention facilitates treatment of brain tumors such as
glioblastoma multiforme.
In yet other preferred embodiments, the enhancing
agent or combination of enhancing agents is co-administered
with the target agent or a combination of target agents 10
minutes prior to, concurrent with, and up to two (2) hours
after administration of the target agent(s). In this fashion,
the maximum dose of cyclosporin enhancer e.g., an amount of
about 30mg/kg of patient body weight, may be administered.
The following examples illustrate various aspects of
the invention and demonstrate the unexpected, very substantial
increase in the oral absorption of paclitaxel achieved. These
examples are not intended, however, to limit the invention in
any way or to set forth specific enhancing or target agents,
dosage ranges, testing procedures or other parameters which
must be used exclusively to practice the invention.
EXAMPLE 1
Six (6) healthy Sprague Dawley rats, all weighing
from 225-275 grams and approximately six to eight weeks old,
received a single oral dose of paclitaxel at 9 mg/kg. Blood
samples were collected from the tail vein of each rat at 0.5,
1, 2, 3, 4 and 6 hours after the paclitaxel dose. The
individual samples were centrifuged and the serum was
separated. For each time interval, the six samples were
composited to produce a single representative sample, All
samples were assayed for unchanged paclitaxel by LC/MS with a
lower limit of quantitation of 50 pg/ml.
The results of the study are graphically illustrated
in the. lower curve of FIG. 1, which indicates that the
bioavailabilitx of the orally administered paclitaxel in serum
was less than lo.
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EXAMPLE 2
Ten (10) healthy Sprague Dawley rats with the same
characteristics as those used in the study described in
Example 1 were treated with 5 mg/kg of oral cyclosporin A
followed later with another 5 mg/kg dose of oral cyclosporin A
and 9 mg/kg of oral paclitaxel.
Blood samples were collected from the tail vein of
each rat at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 and 24
hours after paclitaxel administration. After appropriate
treatment of the samples and the creation of one composite
sample for the group, the plasma from each sample was assayed
for unchanged paclitaxel.
The results of this study are graphically
illustrated in the upper curve of FIG. 1. It may be observed
that the plasma levels of paclitaxel in this group of animals
was several times higher during the first six hours than in
the rats of Example 1 who received paclitaxel alone, that
levels at or above the "target" therapeutic levels were
maintained for (8) eight hours after dosing and that
significant plasma levels were maintained throughout the 24-
hour period.
EXAMPLE 3
A 71-year old man with prostate cancer for three
years agreed to receive an oral dose of paclitaxel and an
enhancer in the form of cyclosporin A. His body surface area
was 2.04 square meters and his weight was approximately 84
kilograms. After an overnight fast, he received two doses of
cyclosporin A (Sandimmune 5 mg/kg) one hour apart. Just after
the second dose, the patient drank a Cremophor/alcohol-based
solution dose of paclitaxel containing 180 mg dissolved in 120
ml of 5o dextrose in water, i.e., about 2.0 mg/kg of body
weight or about 90 mg/mz of body area. Standard
premedications, as one would use for short-term infusion of
taxanes, were not given. After drinking the solution, the
patient remarked that the taste was unpleasant. He
experienced some loose stools for a few hours. He also
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reported some flushing several hours after dosing which might
have been related to the temporary cessation of his anti-
hypersensitive medication. His clinical course was otherwise
unremarkable.
Plasma samples were obtained at frequent intervals
following the administration of paclitaxel and were assayed by
LC/MS/MS. The plasma level results over time are shown in
FIG. 2. Peak was reached about 4 hours post dosing and levels
above 0.07 micromolar were achieved from about one to five
hours. Levels comparable to those found in breast cancer
patients receiving 96-hour intravenous infusions of paclitaxel
(0.05 micromolar), were present for about 10-12 hours (Seidman
et al., J. Clin. Oncol. 14:1877, 1996).
EXAMPLE 4
A 75-year old man with prostate cancer for several
years received an oral dose of paclitaxel and cyclosporin A.
His body surface area was 1.82 square meters and his weight
was approximately 72 kilograms. After an overnight fast, he
received the same regimen of cyclosporin A (Sandimmune 5
mg/kg) and oral paclitaxel (180 mg) as the patient in Example
1, which equaled about 2.5 mg/kg or about 100 mg/mz of
paclitaxel in this patient. Again, standard premedications,
as one would use for short-term infusions of taxanes, were not
given. After drinking the solution, the patient remarked that
the taste was unpleasant. He experienced some loose stools
for a few hours. He also had a modest decline in blood
pressure after dosing which may have been related to a vaso-
vagal reaction secondary to his fasting state and blood draws.
As a precaution the patient received about 100 ml of saline
intravenously. After eating lunch he felt much better and the
remainder of his clinical course was otherwise remarkable.
Plasma samples were obtained at frequent intervals
following the administration of paclitaxel and were assayed by
LC/MS/MS. The plasma level results over time are shown in
FIG. 3. The peak level was almost 0.3 micromolar and occurred
at a_ hours post dosing. Levels above 0.07 micromolar were
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achieved from about one to ten hours. Again, levels
comparable to those found in breast cancer patients receiving
96-hour i ntravenous infusions of paclitaxel, were present for
about 12-15 hours.
FIG. 4 represents a composite of the paclitaxel
concentration levels determined over time in rats (upper curve
from FIG. 1) and in humans (curves from FIGS. 2 and 3)
following oral administration of paclitaxel and two doses of
oral cyclosporin spaced one hour apart, in accordance with the
present invention.
EXAMPLE 5
Fifty-three (53) human patients with incurable
malignancies received oral paclitaxel in combination with CsA
on one occasion and, intravenous (i.v.) paclitaxel at a dose
of 175 mg/m2 as a 3-hour infusion on another. The oral and
i.v. formulation of paclitaxel consisted of 6mg/ml paclitaxel,
dissolved in CREMOPHOR~ EL and ethanol 1:1 w/v. Patients
received one of 9 dose levels. (See FIG. 5.) Dose levels 1 and
2 were randomized for either oral and i.v. administration. At
all higher levels (3-9), patients received oral paclitaxel
during course 1 and i.v. paclitaxel during course 2.
Prior to oral paclitaxel administration, patients
received oral doses of CsA. Patients received one of 10 dose
levels (FIG. 5). At dose levels 2-3, patients received an
oral solution of CsA 10 minutes before receiving oral
paclitaxel. At subsequent doses, CsA was administered in
capsules 30 minutes before paclitaxel administration. At dose
level 4, CsA was administered 10 minutes before and 2 hours
after oral paclitaxel administration.
To prevent, hypersensitivity, patients were
premedicated with dexamethasone 20 mg orally, 12 and 6 hours
prior to i.v. and oral paclitaxel administration, clemastine 2
mg i.v. and cimetidine 300 mg i.v. 30 minutes before i.v. and
oral paclitaxel administration. Three patients at dose level
8 and all patients at dose level 9 did not receive the above
premedication prior to oral paclitaxel administration because
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r~o CREMOPHOR~ EL was detected in plasma of patients treated at
the lower doses of paclitaxel. To prevent nausea and
vomiting, patients at dose levels 8 and 9 were given
grarisertrcn (Kytril~)lmg orally 1 hour prior to receiving
CsA.
Paclitaxel levels in urine and plasma were
determined using a validated a high performance liquid
chromatography (HPLC) assay. CsA levels were determined from
whole blood samples using fluorescence polarization
immunoassay. Ethanol levels were measured from plasma using a
gas chromatagraph. CREMOPHOR~ EL levels were determined using
validated HPLC.
The area under the concentration-time curve (AUC)
was estimated by the trapezoidal rule with extrapolation to
infinity using the terminal rate constant K. The terminal
half-life (t1/2) was calculated as 0.693/k. Other parameters
assessed were maximal concentration (Cmax), the time to
maximal concentration (Tmax) and time spent above threshold
concentrations of 0.05~,M and 0.1~,M (T>0.05~M, T>O.1~M). Cmax
and Tmax were determined graphically. T> 0.05~.M and T> O.l~tM
were determined using linear logarithmic interpolation. The
percentage of the administration dose recovered (LTeXer) was
calculated as the amount excreted in the urine divided by the
actual administration dose multiplied by 1000. Statistical
analysis of the data was performed using the Student's t-test
and the Pearson correlation coefficient. A p value less than
0.05 was regarded as statistically significant.
The principal types of hematological toxicity after
oral administration of paclitaxel were leukocytopenia and
granulocytopenia (FIG. 6). These toxicities were short
lasting and often pre-existing. The non-hematological
toxicities after oral paclitaxel administration, shown in
Figs. 7A and 7B, were nausea, vomiting and arthralgia/myalgia,
and were generally mild. Any severe toxicities were short-
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lived and uncomplicated. Toxicities commonly associated with
CsA were not observed.
Pharmacokinetic parameters of oral paclitaxel
administration are defined ir~ FIG. 8. Dose escalation of. oral
paclitaxel from 60mg/m- to 120mg/m' in combination with CsA
l5mg/kg resulted in significant increase in both AUC and
T>O.1~M of paclitaxel. Mean AUC values for the doses 60mg/m2
and 120 mg/m' were 1.65+/- 0.93~,M/h and 2.55 +/- 2.29~M/h,
respectively and mean T>0.1 ~.M were 3.7+/- 2.3h and 7.9 +/-
8.Oh, respectively. Further dose increase of oral paclitaxel
did not result on average in an additional significant
increase in AUC or T>0.1 ~M of paclitaxel. Increasing the CsA
dose or splitting the dose did not result in a further
increase in the AUC and T> 0.1 ~,M of paclitaxel compared to
the single dose of l5mg/kg. Large inter-patient variability
was observed at all dosage levels.
Pharmacokinetic parameters of CsA are defined in
FIG. 9. Dose increment and scheduling of CsA resulted in
higher AUC values of CsA but Cmax values were not increased.
Dose escalation of paclitaxel did not produce significant
differences in pharmacokinetics of CsA. CREMOPHOR~ EL levels
in plasma after oral administration of paclitaxel were
undetectable at all paclitaxel dose levels (< O.Ola v/v).
The i.v. paclitaxel pharmacokinetic data were in
agreement with previously observed results.
In summary, CREMOPHOR~ EL, which can induce
hypersensitivity in patients, is not absorbed through the gut
when administered orally as a solvent agent for paclitaxel.
Additionally, CREMOPHOR~ EL may interfere with the absorption
of paclitaxel thereby limiting the bioavailability of this
drug. No hypersensitivity was observed in patients who did
not receive premedication prior to oral paclitaxel
administration. Therefore, paclitaxel can be administered
orally without the consequence of hypersensitivity. In
addition, the maximum effect of CsA on the enhancement of the
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exposure to paclitaxel was observed at a single dose of CsA of
l5mg/kg.
As various possible embodiments might be made of the
above invention and as various changes might be made in tine
embodiments set forth above, it is to be understood that all
matters herein described are to be interpreted as illustrative
and not in a limiting sense.
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