Note: Descriptions are shown in the official language in which they were submitted.
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-1
METHOD OF TREATMENT
This invention relates to a method of treating the weight of patients and is
particularly
concerned with a method of treating the weight of patients suffering from
psychoses.
Schizophrenia is a chronic and debilitating illness that affects approximately
1% of the
population worldwide. For many years, conventional antipsychotic agents have
been widely
used to treat schizophrenia; however, they are associated with undesirable
motor symptoms
(extrapyramidal symptoms [EPS]) such as akathisia, dyskinesia, bradykinesia
and
parkinsonism, which are known to contribute to poor compliance with treatment.
Such
1o adverse effects of the older, typical antipsychotics caused a great deal of
distress to patients
but were tolerated as being inevitable in the treatment of psychotic symptoms.
Even so,
studies have suggested that 40% of patients stopped taking their medication
within 1 year and
75% of patients stopped within 2 years (Perkins, 1999, J. Clinical Psychiatry
60 (suppl. 21),
pp 25-30).
Many of the newer, atypical antipsychotic agents have an improved tolerability
profile.
With the resulting diminution in prevalence of the very debilitating EPS, more
attention is
being focused on other side effects of these agents, including a propensity to
induce weight
gain, seen with most atypical antipsychotics to a greater or lesser degree
(Wirshing et al, 1999,
J. Clinical Psychiatry 60: 358-63). In some cases, this may adversely affect
patients' quality
of life and possibly treatment compliance.
It has been recognized for more than 40 years that there is an association
between
antipsychotic medication and weight gain. In the past, weight gain has been
linked to efficacy
of antipsychotic medication, with research linking a positive outcome with
increased weight.
However, more recent research has shown this not to be the case (Umbricht et
al, 1994, J.
Clinical Psychiatry 55 (suppl. B): 157-60; Bustillo et al, 1996, American J.
Psychiatry 153:
817-9).
Weight gain is associated with increased morbidity and mortality from a wide
range of
conditions including hypertension, coronary heart disease, cerebrovascular
disease, type 2
diabetes mellitus, various cancers, sleep apnea and respiratory problems. It
is also linked with
3o morbidity related to the disease being treated itself. Studies have shown
that the side effect of
weight gain causes relatively more distress than many of the other common side
effects
associated with antipsychotic medication (Weiden, 1999). If weight gain is
considered by the
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-2-
patient to be unacceptable, compliance with the antipsychotic may be reduced
and a
worsening of the psychotic condition may ensue.
The extent to which each of these antipsychotic agents is associated with
weight gain
varies considerably (Allison et al, 1999, Am. J. Psychiatry 156: 1686-96;
Wirsching et al,
1999). Weight gains of 3.99, 3.51 and 2.00 kg have been estimated following 10
weeks
treatment with clozapine, olanzapine and risperidone, respectively (Allison et
al, 1999).
Simansky et al, (Am. Psychiatry Association Meeting, Washington, USA, May,
1999)
report on weight gains associated with treatment using ziprasidone,
risperidone, quetiapine,
olanzapine or clozapine. They confirm that the largest weight gains are
associated with
1 o treatment using olanzapine or clozapine. They report that quetiapine is
associated with a
weight gain greater to that seen with risperidone and greater than that seen
with ziprasidone.
However, this report is based on an extrapolation to a ten week period based
on an estimate at
week 6 of treatment.
We have unexpectedly found that quetiapine is associated with a small mean
weight
15 increase in the first 5-6 weeks of treatment with little further mean
change observed over 12
months of treatment. Actual mean weight increase for quetiapine treated
patients differs
markedly from the extrapolated figures reported by Simansky et al.
According to the present invention, there is provided a method of treating the
weight
of a patient which comprises administering an effective amount of quetiapine
or a
2o pharmaceutically acceptable salt thereof to said patient.
In another aspect, the present invention provides quetiapine or a
pharmaceutically
acceptable salt thereof for use in treating the weight of a patient.
In yet a further aspect, the present invention provides the use of quetiapine
or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament
for treating the
25 weight of a patient.
Quetiapine is 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
dibenzo[b,fJ[1.4]thiazepine. This compound pharmaceutically acceptable salts
thereof and
use in treating schizophrenia are described in granted European Patent No. EP
240,228.
In particular, the patient is suffering from psychoses.
3o It is well recognized that there is a link between obesity and diabetes,
especially type II
diabetes, and that moderate to severe obesity increases the risk of developing
diabetes. It is
also widely accepted that weight loss results in metabolic improvement and
hence in
glycaemic control and insulin sensitivity which in turn give rise to
improvements in
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-3-
cardiovascular risk factors. This is reported by, for example, Bosello et al,
Int. J. of Obesity,
(1997) 21, Suppl 1, S10-13.
Weight gain in patients is generally undesirable but is more so in patients
who are
diabetic or who are at risk from developing diabetes.
Accordingly, the present invention further provides a method of treating the
weight of
a patient who is exhibiting diabetes or is at risk from developing diabetes
which method
comprises administering an effective amount of quetiapine or a
pharmaceutically acceptable
salt thereof to said patient. In particular, the patient is suffering from
psychoses.
In an alternative aspect of the present invention, there is also provided a
method of
1o treating psychoses in a patient who is diabetic or who is at risk from
developing diabetes
which method comprises administering an effective amount of quetiapine or a
pharmaceutically acceptable salt thereof to said patient.
In particular the patient is diabetic, that is exhibiting one or more of the
symptoms of
diabetes.
15 Quetiapine and pharmaceutically acceptable salts thereof are particularly
effective in
inducing weight loss in patients who have tended to gain weight when treated
with other
antipsychotics such as clozapine or olanzapine, in particular clozapine. Under
such
circumstances, quetiapine or pharmaceutically acceptable salts thereof may
reverse at least
part of any weight gained as a result of treatment with the antipsychotic such
as clozapine or
20 olanzapine, in particular clozapine.
In a particular aspect, the dosage of the other antipsychotic agent, such as
clozapine or
olanzapine, is decreased during treatment with quetiapine or pharmaceutically
acceptable salt
thereof.
The method of treatment of the present invention relates to short term (5-6
weeks),
25 medium term (1-6 months) and long term (6 months-2 years or more)
treatment, and is
particularly valuable in medium term and long term treatment.
Quetiapine may be administered as the compound, 11-(4-[2-(2-
hydroxyethoxy)ethyl]-
1-piperazinyl)-dibenzo[b,f][1.4]thiazepine or may be administered in the form
of a
pharmaceutically acceptable salt. Examples of suitable salts include, for
example, chloride,
3o maleate, fumarate, citrate, phosphate, methane sulphonate and sulphate
salts. Preferred salts
include fumarates and a particularly preferred salt is the hemi-fumarate.
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-4-
It is generally preferred that 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
dibenzo[b,f][1.4]thiazepine is administered in the form of a pharmaceutically
acceptable salt,
and in particular a fumarate (2:1) salt.
In the treatment of the diseases and conditions mentioned above quetiapine or
a
pharmaceutically acceptable salt may be administered orally or parenterally in
a conventional
dosage form such as tablets, pills, capsules, injectables or the like. The
dosage in mg/kg of
body weight of the compound used to treat mammals will vary according to the
size of the
mammal and particularly with respect to the brain/body weight ratio. In
general, a higher
mg/kg dosage for a small animal such as a dog will have the same effect as a
lower mg/kg
to dosage in an adult human. A minimum effective dosage for quetiapine or a
pharmaceutically
acceptable salt thereof will be at least about 1.0 mglkg of body weight per
day for mammals
with a maximum dosage for a small mammal such as a dog, of about 200 mg/kg per
day.
For humans, a dosage of about 1.0 to 40 mg/kg per day will generally be
effective.
Typically, a dosage of about 25mg to 800mg per day will generally be
effective.
Usually, a dosage of about 150mg to 750mg per day will be administered, with a
convenient
dosage being about 300mg per day. In some groups of patients a lower dosage
may be
preferred such as 100mg per day. The dosage can be given once daily or in
divided doses, for
example, 2 to 4 doses daily. The dose may be conventionally formulated in an
oral or
parenteral dosage form by compounding 25 to 500 mg per unit dosage of
conventional
2o vehicle, excipient, binder, preservative, stabilizer, flavor or the like as
called for by accepted
pharmaceutical practice, for example, as described in US Patent 3,755,340.
Quetiapine or a pharmaceutically acceptable salt may be used in pharmaceutical
compositions as the sole active ingredient or may be contained in a
pharmaceutical
composition together with one or more other active ingredients, or it may be
co-administered
with one or more known drugs.
Quetiapine or a pharmaceutically acceptable salt may be administered in
conjunction
with one or more other agents useful for treating diabetes.
Quetiapine or a pharmaceutically acceptable salt may be administered in
conjunction
with one or more other agents useful for treating psychoses.
3o As indicated above, where quetiapine or a pharmaceutically acceptable salt
is
administered in conjunction with another agent it may be administered
simultaneously,
sequentially or separately with that other agent or agents. Thus, as indicated
above, quetiapine
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-5-
or a pharmaceutically acceptable salt may be formulated with the other agent
or agents or may
be presented as a separate formulation.
Thus, in one aspect of the present invention, there is provided a
pharmaceutical
composition comprising quetiapine or a pharmaceutically acceptable salt and an
agent known
for treating diabetes together with a pharmaceutically acceptable diluent or
Garner.
In a further aspect there is provided a pharmaceutical composition comprising
quetiapine or a pharmaceutically acceptable salt and an agent for treating
diabetes for
simultaneous, sequential or separate administration.
The preparation of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
1o dibenzo[b,fJ[1.4]thiazepine and its pharmaceutically acceptable salts is
described in, for
example, granted European Patents Nos. EP 240,218; EP 282,236 and in
International Patent
Application No. PCT/GB98/02260. This compound is commercially available under
the
generic name quetiapine fumarate.
The invention will now be illustrated with reference to the following, non-
limiting
examples in which quetiapine was used as the fumarate (2:1 ) salt..
Examine 1
Body weight data were collected for a group of 65 randomly-selected
schizophrenic
patients who were on clozapine initially (200 - 800 mg/day for 6 months) and
then had
2o quetiapine added to their therapy. Weights were recorded monthly, and
status of diabetes
follow-up was also performed. Clozapine dosages were reduced as quetiapine was
added.
The duration of treatment with quetiapine was 10 months. Data were extracted
from
retrospective chart review of 65 patients who were prospectively assigned to
clozapine-
quetiapine therapy. All 65 patients showed weight loss ranging from 0.5 to 23
lbs, with a
mean loss of 3.98 lbs, after the first month of combination treatment; the
quetiapine dose at
one month ranged from 200 - 800 mg/day. The improvement continued throughout
the 10
month study period. Total weight loss ranged from 1 to 41 lbs, with a mean
loss of 9.2 lbs
over the course of the study. Twenty per cent of patients developed diabetes
during clozapine
monotherapy and each showed significant improvement of diabetes with addition
of
3o quetiapine, as assessed through monthly blood monitoring and clinical
improvement.
Thus, an unexpected clinical effect of quetiapine is its apparent propensity
to induce
weight loss and help with diabetes management in patients who gain weight and
develop
diabetes on clozapine.
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
-6-
Example 2
427 patients (277 male; 150 female) were treated with quetiapine monotherapy
during
controlled and open-label extension studies for up to 3.5 years and weight
changes were
monitored at specified time intervals throughout this period. The patients
were in the age
range 18-75 with a mean age of 37.3 years.
Patients were grouped using an observed cases approach within specified time
intervals. Data on patients who received quetiapine monotherapy during the
controlled
portion of the trial and/or quetiapine during the open-label extension period
are reported. Data
were obtained for 30% of patients for at least one year.
1o Over the first 4 weeks, a mean weight loss of 0.36 Kg (n=17) was recorded.
At
subsequent time intervals weight changes were -0.17 kg (n=49) at weeks 5-8;
+1.58 kg
(n=171) at weeks 9-13; +0.29 kg(n=153) at weeks 14-26; +1.73 kg (n=128) at
weeks 27-39;
-1.47 kg (n=37) at weeks 40-52; +2.00 kg (n=116) at weeks 53-78; +3.43 kg
(n=64) at weeks
79-104; +3.45 kg (n=44) at weeks 105-130 and +0.36 kg (n=9) at weeks 131-156.
Patients
received a mean quetiapine dosage of approximately 475 mg/day after one year
of open-label
treatment. Only one patient withdrew from the open-label study due to an
adverse event of
weight gain.
Thus, an unexpected clinical effect of quetiapine is its apparent capability
of being
associated with minimal weight gain unlike olanzapine and clozapine.
Example 3
The following illustrates representative pharmaceutical dosage forms
containing the
compound 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
dibenzo[b,f][1,4]thiazepine
fumarate (2:1 ).
(a) Tablet m tablet
Quetiapine fumarate .............................. 50.0
Mannitol, USP................................. 223.75
Croscarmellose sodium........................ 6.0
Maize starch................................. 15.0
3o Hydroxypropylmethylcellulose (HPMC), 2.25
Magnesium stearate........................... 3.0
CA 02363784 2001-10-31
WO 00/71106 PCT/GB00/01875
(b) Capsule
Quetiapine fumarate................................... 10.0
Mannitol, USP............................... 488.5
Croscarmellose sodium........................ 15.0
Magnesium stearate........................... 1.5
The above formulations may be obtained by conventional procedures well known
in
the pharmaceutical art. The tablets may be enteric coated by conventional
means, for example
to provide a coating of cellulose acetate phthalate.
1o A preferred formulation is that available commercially as quetiapine
fumarate.
