Note: Descriptions are shown in the official language in which they were submitted.
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The present'invention relates to prevention of
diarrhea caused by administration to a patient of irinotecan or
a pharmaceutically acceptable salt of irinotecan.
Background of the Invention
Irinotecan and its preparation are known, for
instance, from United States Patent No. 4,604,463. Irinotecan
has the chemical name [1,4'-Bipiperidine]-1'-carboxylic acid(S)-
4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-
pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester; and has
the following structure
N CH3
N I1 0 / \ O
N
O \ ~ /
O
H3C~.,,,,,,
OH O
Irinotecan, in the form of its hydrochloride, is
available commercially as Camptosar* Injection from Pharmacia
and Upjohn. Irinotecan hydrochloride trihydrate is a pale
yellow to yellow crystalline powder, with the empirical formula
C33H3gN406~HC1~3H20 and a molecular weight of 677.19.
Irinotecan hydrochloride was clinically investigated as CPT-11.
* Trade-mark
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Irinotecan izydrochloride has shown activity against a
variety of tumour types, particularly refractory colorectal
tumours, and it is used for the treatment of various forms of
cancer. Its primary use is in the treatment of colon cancer,
particularly advanced colon cancer. It is also of interest for
treatment of other cancers, however, and mention is made of
cancers of the lung, the stomach and the pancreas.
Irinotecan is usually administered in one of two
treatment regimens. In one regimen, a dose of 125mg/m2 of
irinotecan is given i.v. over a 90 minute period each week for
four weeks. After a lapse of two weeks this is repeated, so
that the patient receives irinotecan in four weeks out of every
six. In the other treatment regimen a dose of 350 mg/m2 is
given i.v. over 90 minutes, every third week. Thus, the one
regimen operates with a six week cycle and the other regimen on
a three week cycle.
It is found that administration of irinotecan causes
diarrhea in some patients. The occurrence of diarrhea is
unpredictable, but in a significant number of cases the diarrhea
is severe. In some cases the effect of the diarrhea on the
general health of the patient is so severe that the treatment
with irinotecan has to be terminated.
Diarrhea often develops as a side-effect disorder
during the clinical treatment with chemotherapeutic agents,
whose typical symptom is characterized by the frequent
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defecation of liquid or liquid-like stools. This adverse effect
is prevalently associated with, e.g., the use of 5-fluorouracil,
cisplatin and CPT-11. In particular, late diarrhea due to the
administration of CPT-11 can be prolonged, may lead to
dehydration and electrolyte imbalance and can be, in some cases,
so serious that CPT-11 administration should be interrupted and
dose may need to be reduced.
So far, no definite and efficacious means for
prevention and/or treatment of CPT-11-induced diarrhea have been
currently identified. Thus, there is a need to develop an agent
for preventing and/or treating diarrhea, particularly late
diarrhea, caused by CPT-11 administration, which has good safety
and efficacy.
Summary of the Invention
It has now been discovered that diarrhea can be
avoided or alleviated if carbon is also administered to a
patient who is receiving irinotecan.
Accordingly, in one aspect of the invention there is
provided a method of avoiding or alleviating irinotecan-induced
diarrhea in a patient in need thereof, which method comprises
administering carbon to the patient.
In another aspect the invention provides the use of
carbon for avoiding or alleviating irinotecan-induced diarrhea.
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Description of the Preferred Embodiments
In the present specification, the term "irinotecan"
includes not only the free base but also pharmaceutically
acceptable salts of irinotecan, for example the hydrochloride
salt.
In accordance with the invention, a patient who is
receiving irinotecan or a pharmaceutically acceptable salt of
irinotecan is also given carbon. The irinotecan can be given in
the unsalified form, or in the form of a pharmaceutically
acceptable salt. Mention is made of irinotecan hydrochloride
(CPT-11) especially irinotecan hydrochloride trihydrate. The
carbon is suitably in activated form, and activated charcoal in
a form suitable for administration to humans is available.
The major dose-limiting toxicity in cancer patients
receiving CPT-11 therapy is a severe delayed chronic grade 3-4
diarrhea. The loss of fluids and electrolytes associated with
persistent and severe diarrhea, such as late diarrhea occurring
more than 24 hours after administration of CPT-11, can result in
life-threatening dehydration, renal insufficiency, and
electrolyte imbalances. Fluctuation in intravascular fluids
caused by severe diarrhea may result in cardiovascular
morbidity. The life-threatening aspects of persistent or severe
diarrhea require aggressive treatment and often lead to
hospitalization. Persistent and severe diarrhea can also have
tremendous negative effect on the patient's quality of life, and
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interferes with roles and responsibilities and interpersonal
relationships and promotes feelings of social isolation.
Quick resolution or, more preferably, prevention of
diarrhea is important, not only to prevent hospitalization, but
also to improve quality of life and to enable patients to
continue chemotherapy treatment to effect a remission or cure.
A variety of strategies for the control of chemo-
therapeutic-related diarrhea, particularly for the control of
diarrhea induced by CPT-11, have been examined in humans and in
animal models.
In humans, aggressive high-dose co-therapy with
loperamide (an agent that slows intestinal motility and affects
water and electrolyte movement through the bowel) has been used
to reduce or control diarrhea (Rougier P, Bugat R. CPT-11 in the
treatment of colorectal cancer: clinical efficacy and safety
profile. Semin Oncol 1996; 23(Suppl 3): 34-41.) Though
partially successful in some cases, this agent requires
administration at 2 hr intervals at the onset of diarrhea and is
not used prophylactically.
The present situation is such that there is not yet
any established efficacious and safe agent, which is suitable in
prophylaxis and/or treatment of diarrhea, especially persistent
and severe diarrhea, such as late diarrhea induced by irinotecan
administration to a cancer patient. It has now been
unexpectedly found that carbon can be utilized in the
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prophylaxis and/or treatment of the diarrhea, especially
persistent and severe diarrhea such as late diarrhea, related to
CPT-11 administration.
Namely, the present invention is directed to a method
for preventing diarrhea caused by the administration of
irinotecan, comprising administering to a patient susceptible to
said diarrhea a therapeutically effective amount of carbon.
The use of carbon in preventing/treating diarrhea
induced by irinotecan according to the present invention has
excellent prophylactic effect. Therefore, use of carbon not
only permits the continuation of a cancer chemotherapy which
would otherwise need to be reduced or even interrupted, but also
provide a marked improvement in the patient's quality of life
and reduces or avoids the risk of hospitalization.
The term "diarrhea" includes persistent and severe
diarrhea, such as diarrhea which occurs more than 24 hours after
irinotecan administration (late diarrhea). Persistent and
severe diarrhea can delay treatment and reduce patient
compliance, and thus interfere with the completion of the full
course of therapy and ultimately increase the cost of care.
In the methods according to the invention, carbon may
be administered simultaneously with irinotecan, or the compounds
may be administered sequentially, in any desired order.
Irinotecan is normally administered intravenously.
Carbon is administered orally, for example in the form of a
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stirred aqueous suspension or in solid chewable form as, say, a
charcoal biscuit. Ideally, for each dose of irinotecan there
are given several doses of carbon, some before, some
simultaneously with and some after the dose of irinotecan.
The dosage ranges for the administration of the carbon
and of the irinotecan may vary with the age, condition, sex and
extent of the disease in the patient and can be determined by
one of skill in the art.
The dosage regimen must therefore be tailored to the
particular of the patient's conditions, response and associate
treatments in a manner which is conventional for any therapy,
and may need to be adjusted in response to changes in conditions
and/or in light of other clinical conditions.
CPT-11 is usually administered in a regimen wherein a
dose of 125 mg/m2 of CPT-11 is given i.v. over a 90 minutes
period once weekly for 4 weeks, followed by a 2-week rest
period. Thereafter, additional courses of treatment may be
repeated every 6 weeks (4 weeks on therapy, followed by 2 weeks
off therapy). Subsequent doses may be adjusted to as high as
150 mg/m2 or to as low as 50 mg/m2 in 25-mg/m2 to 50-mg/m2,
increments depending upon individual patient tolerance of
treatment, as judged by the attending physician.
In one embodiment of the invention the patient is
given charcoal in a stirred aqueous suspension, in a dose of
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30 ml of the suspension containing 1000 mg of charcoal.
Suitably one such dose is given to the patient the night before
the patient is scheduled to receive irinotecan, three such doses
are given on the day that the patient receives the irinotecan
and three such doses are given on the following day. The
patient therefore receives seven doses per dose of irinotecan.
It has been found that this treatment avoids or alleviates
diarrhea in many cases. Of course, different patients show
different response to the treatment, and some departure from
these amount of dose and frequency of dose may be required. The
precise dose to be given to an individual patient, and the
frequency, are matters to be decided by the attending physician
or other medical professional.
The activated carbon can be given in other forms. For
instance charcoal biscuits can be given. The preferred form for
administration will vary from patient to patient and this is
again a matter to be decided by the attending physician or
nursing staff.
The invention extends to a commercial package
containing carbon in a form suitable for oral administration,
together with instructions for its use for preventing or
mitigating irinotecan-induced diarrhea.
The invention further extends to a kit containing
irinotecan and, separately, carbon in a form suitable for oral
administration. The irinotecan and the carbon may each be
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present in one or more unit doses. For instance, the kit may
comprise one unit dose of irinotecan and seven unit doses of
carbon.
When referring to "carbon in a form suitable for oral
administration" we are referring particularly to the degree of
purity of the carbon. Thus, a quantity of pure, finely divided
charcoal that is intended to be made up into an aqueous
suspension is considered to be "in a form suitable for oral
administration" both before and after it is made up into the
suspension.
The invention also relates to combining separate
pharmaceutical compositions in kit form. That is, a kit is
contemplated wherein two separate units are combined: a
irinotecan pharmaceutical composition, optionally also
containing a pharmaceutically acceptable carrier or excipient,
and a unit of carbon in a form suitable for oral administration.
It is therefore a further object of the present
invention to provide a kit comprising a package housing a first
container containing a pharmaceutical composition comprising
irinotecan and a second container containing the carbon.
The kit will preferably include directions for the
administration of the separate components. The kit form is
particularly advantageous when the separate components must be
administered in different dosage forms (e.g. oral and
parenteral) or are administered at different dosage intervals.
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The invention is further illustrated in the following
examples.
A group of 28 patients (cycle 1) completed a first
cycle of therapy in which each patient was treated with
irinotecan hydrochloride in accordance with the first treatment
regimen mentioned above, and was also treated with charcoal.
Thus, each patient was given a dose of 125 mg/m2 of the
irinotecan i.v. on days l, 8, 15 and 22 of 42 day periods. The
doses were given intravenously over 90 minutes. Each patient
10 was also given orally doses of charcoal in stirred aqueous
suspension. Each patient was given one dose on the day before
receiving irinotecan, three doses on the day of receiving
irinotecan and three doses on the day after receiving
irinotecan. Each dose contained 1000 mg charcoal in a 15 ml
aqueous suspension.
Of the group of 28 patients who completed the first
cycle 24 patients (cycle 2) completed a second cycle in which
each patient was treated with irinotecan hydrochloride, in
accordance with the first treatment regimen mentioned above, but
was not treated with charcoal. Thus, each patient was given a
dose of 125 mg/m2 of the irinotecan i.v. on days 1, 8, 15 and 22
of 42 day periods.
The incidence of diarrhea among the patients was noted
and graded, from zero, indicating no diarrhea, to higher numbers
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indicating more severe diarrhea. The results are given in the
following Table.
TABLE
Cycle 1 Cycle 2
CHARCOAL (N=28) NO CHARCOAL (N=24)
Diarrhea Grade 0,1 22 14
Grade 2 4 4
Grade 3 2 3
Grade 4 0 3
Median % Dose delivered (as 0.98 0,
a proportion of that
planned)
#receiving 90s or more of 18/28 9/24
planned dose
#patients taking more than 7/28 13/24
anti-diarrheal tablets
( loperamide )
This table indicates that on the first cycle of
therapy [when charcoal was also given] the incidence of severe
diarrhea was less [2/28 versus 6/24]. In support of this is the
fact that these patients took less anti-diarrheal medication.
In addition these patients were able to receive significantly
10 more irinotecan because of the reduced diarrhea. This could
potentially translate into a higher rate of tumor control
although this was not assessed in this trial.
