U.S. patent application number 12/285117 was filed with the patent office on 2009-02-12 for drug combinations comprising (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri- midin-5-yl](3r,5s)-3, 5-dihydroxyhept-6-enoic acid and an inhibitor, inducer or substrate of p450 isoenzyme 3a4.
Invention is credited to Takahiko Baba, Howard G. Hutchinson, John S. Pears, Ali Raza, Dennis Schneck, Akira Touchi, Yoshitaka Yamaguchi.
Application Number | 20090042911 12/285117 |
Document ID | / |
Family ID | 27269637 |
Filed Date | 2009-02-12 |
United States Patent
Application |
20090042911 |
Kind Code |
A1 |
Pears; John S. ; et
al. |
February 12, 2009 |
Drug combinations comprising
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-YL](3R,5S)-3, 5-dihydroxyhept-6-enoic acid and an
inhibitor, inducer or substrate of P450 isoenzyme 3A4
Abstract
The invention concerns safe non-interacting drug combinations of
a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitor, which is
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof (the Agent) and a drug
which is either an inducer, inhibitor or a substrate of cytochrome
P450, in particular cytochrome P450 isoenzyme 3A4. Particular
combinations are useful in treating hyperlipidaemia in humans who
are receiving immunosuppressive chemotherapy. A preferred
combination is the Agent and a fibrate drug, the use of such a
combination in treating hyperlipidaemia in mammals, and medicaments
containing such a combination for use in such treatments.
Inventors: |
Pears; John S.;
(Macclesfield, GB) ; Raza; Ali; (Wilmington,
DE) ; Hutchinson; Howard G.; (Wilmington, DE)
; Schneck; Dennis; (Wilmington, DE) ; Baba;
Takahiko; (Toyonaka-shi, JP) ; Touchi; Akira;
(Toyonaka-shi, JP) ; Yamaguchi; Yoshitaka;
(Toyonaka-shi, JP) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Family ID: |
27269637 |
Appl. No.: |
12/285117 |
Filed: |
September 29, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11079530 |
Mar 15, 2005 |
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12285117 |
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Current U.S.
Class: |
514/256 ;
514/512 |
Current CPC
Class: |
A61P 3/06 20180101; A61P
9/00 20180101; A61K 45/06 20130101; A61P 9/10 20180101; A61K 31/365
20130101; A61P 43/00 20180101; A61P 37/06 20180101 |
Class at
Publication: |
514/256 ;
514/512 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 31/216 20060101 A61K031/216 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 6, 1999 |
GB |
9902593.4 |
Sep 8, 1999 |
GB |
9921063.5 |
Sep 8, 1999 |
GB |
9921064.3 |
Claims
1. A non-interacting drug combination comprising a HMG-CoA
reductase inhibitor, which is
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof and a drug which is an
inhibitor, inducer or substrate of P450 isoenzyme 3A4.
2. A non-interacting drug combination, as claimed in claim 1,
wherein the second drug is an inhibitor or inducer of P450
isoenzyme 3A4.
3. A non-interacting drug combination, as claimed in either claim 1
or claim 2, wherein each drug is administered together or each drug
is administered sequentially.
4. A non-interacting drug combination, as claimed in any claim from
1 to 3, wherein the second drug is used to lower cholesterol and is
an inducer, inhibitor or substrate of P450 isoenzyme 3A4.
5. A non-interacting drug combination, as claimed in claim 4,
wherein the second drug is selected from bezafibrate, clofibrate,
fenofibrate, gemfibrozol and niacin.
6. A non-interacting drug combination, as claimed in claim 5,
wherein the second drug is fenofibrate.
7. A non-interacting drug combination, as claimed in any claim from
1 to 3, wherein the second drug is used in treating cardiovascular
conditions and is also an inhibitor, inducer or substrate of P450
isoenzyme 3A4.
8. A non-interacting drug combination, as claimed in claim 7,
wherein the second drug is selected from digitoxin, diltiazem,
losartan, nifedipine, quinidine, verapamil and warfarin.
9. A non-interacting drug combination, as claimed in any claim from
1 to 3, wherein the second drug is used in immunosuppression
therapy and is an inducer, inhibitor or substrate of P450 isoenzyme
3A4.
10. A non-interacting drug combination, as claimed in claim 9,
wherein the second drug is selected from cyclosporin, tacrolimus
and a corticosteroid.
11. A non-interacting drug combination, as claimed in any claim
from 1 to 10, wherein
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof is dosed at 5, 10, 20, 40
or 80 mg once per day.
12. A pharmaceutical formulation comprising
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof, a drug which is an
inducer, inhibitor or substrate of P450 isoenzyme 3A4 and a
pharmaceutically-acceptable diluent, carrier or adjuvant.
13. A pharmaceutical formulation, as claimed in claim 12, wherein
the second drug is a substrate of P450 isoenzyme 3A4 and is
selected from acetominophen, aldrin, aflentanil, amiodorane,
astemizole, benzphetamine, budenoside, carbamazepine,
cyclophosphamide, cyclosporin, dapsone, digitoxin, ditiazem,
diazepam, erthromycin, etoposide, flutamide, hydroxyarginine,
ifosphamide, imipramine, lansoprazole, lidocaine, lovatidine,
losartan, lovastatin, midrazolam, nifedipine, omeprazole,
quinidine, rapamycin, retenoic acid, steroids, tacrolimus,
teniposide, theophyline, toremifene, triazolam, troleandomycin,
verapamil, warfarin, zatosetron and zonisamide.
14. A pharmaceutical formulation, as claimed in claim 12, wherein
the second drug is an inhibitor of P450 isoenzyme 3A4 and is
selected from clotrimazole, ethinylestradiol, gestodene,
itraconazole, ketoconazole, miconazole, diltiazem, naringenin,
erthromycin, cyclosporin and triacetyloleandomycin.
15. A pharmaceutical formulation, as claimed in claim 12, wherein
the second drug is an inducer of P450 isoenzyme 3A4 is selected
carbamazepine, dexamethasone, phenobarbital, phenyloin, rifampin,
sulfadimidine, sulfinipyrazone and triacetyloleandomycin.
16. A pharmacy pack comprising a first drug which is
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof and a second drug which is
an inducer, inhibitor or substrate of P450 isoenzyme 4A4.
17. A pharmacy pack, as claimed in claim 16, wherein the second
drug is used to lower cholesterol and is an inducer, inhibitor or
substrate of P450 isoenzyme 3A4.
18. A pharmacy pack, as claimed in claim 17, wherein the second
drug is selected from bezafibrate, clofibrate, fenofibrate,
gemfibrozol and niacin.
19. A pharmacy pack, as claimed in claim 16, wherein the second
drug is used in treating cardiovascular conditions and is also an
inhibitor, inducer or substrate of P450 isoenzyme 3A4.
20. A pharmacy pack, as claimed in claim 19, wherein the second
drug is selected from, digitoxin, diltiazem, losartan, nifedipine,
quinidine, verapimil and warfarin.
21. A pharmacy pack, as claimed in claim 16, wherein the second
drug is a substrate of P450 isoenzyme 3A4 and is selected from
acetominophen, aldrin, aflentanil, amiodorane, astemizole,
benzphetamine, budenoside, carbamazepine, cyclophosphamide,
cyclosporin, dapsone, digitoxin, ditiazem, diazepam, erthromycin,
etoposide, flutamide, hydroxyarginine, ifosphamide, imipramine,
lansoprazole, lidocaine, lovatidine, losartan, lovastatin,
midrazolam, nifedipine, omeprazole, quinidine, rapamycin, retenoic
acid, steroids, tacrolimus, teniposide, theophyline, toremifene,
triazolam, troleandomycin, verapamil, warfarin, zatosetron and
zonisamide.
22. A pharmacy pack, as claimed in claim 16, wherein the second
drug is an inhibitor of P450 isoenzyme 3A4 and is selected from
clotrimazole, ethinylestradiol, gestodene, itraconazole,
ketoconazole, miconazole, diltiazem, naringenin, erthromycin,
cyclosporin and triacetyloleandomycin.
23. A pharmacy pack, as claimed in claim 16, wherein the second
drug is an inhibitor of P450 isoenzyme 3A4 and is selected from
carbamazepine, dexamethasone, phenobarbital, phenyloin, rifampin,
sulfadimidine, sulfinipyrazone and triacetyloleandomycin.
24. Use of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof in the preparation of a
medicament for use in combination therapy with a second drug which
is an inducer, inhibitor or substrate of P450 isoenzyme 3A4.
25. Use of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof in the preparation of a
medicament for use in cholesterol lowering therapy in combination
therapy with a second drug which is an inducer, inhibitor or
substrate of P450 isoenzyme 3A4.
26. Use, as claimed in claim 25, wherein the second drug is
selected from bezafibrate, clofibrate, fenofibrate, gemfibrazol and
niacin.
27. Use of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof in the preparation of a
medicament for use in the treatment of cardiovascular condition in
combination with a second which is an inducer, inhibitor or
substrate of P450 isoenzyme 3A4.
28. Use, as claimed in claim 27, wherein the second drug is
selected from digitoxin, diltiazam, losartan nifedipine, quinidine,
verapimil and warfarin.
29. Use of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof in the preparation of a
medicament for use in cholesterol lowering therapy in a patient
receiving immunosuppressive therapy.
30. Use, as claimed in claim 29, wherein the immunosuppressive
therapy comprises the administration of a drug selected from
cyclosporin, tacrolimus and a corticosteroid.
31. Use of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof in the preparation of a
medicament for use in cholesterol lowering therapy in combination
with a second drug which is selected from bezafibrate, clofibrate,
fenofibrate, gemfibrazol and niacin in a patient receiving
immunosuppressive therapy.
32. Use as claimed in claim 31 wherein the immunosuppressive
therapy comprises the administration of a drug selected from
cyclosporin, tacrolimus and a corticosteroid.
Description
[0001] The invention concerns safe non-interacting drug
combinations of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitor, which is
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof (the Agent) and a drug
which is either an inducer, inhibitor or a substrate of cytochrome
P450, in particular cytochrome P450 isoenzyme 3A4. Particular
combinations are useful in treating hyperlipidaemia in humans who
are receiving immunosuppressive chemotherapy. A preferred
combination is the Agent and a fibrate drug, the use of such a
combination in treating hyperlipidaemia in mammals, and medicaments
containing such a combination for use in such treatments.
[0002] Hypercholesterolaemia is one of the strongest risk factors
for atherosclerosis which is associated with coronary artery
disease (including angina pectoris, myocardial infarction and
mortality), stroke (including cerebro vascular accident and
transient ischaemic attack) and peripheral arterial occlusive
disease. Several types of hypercholesterolaemia exist. The
magnitude of hypercholesterolaemia may have consequences for the
therapy, but in general, any reduction of elevated plasma
cholesterol levels is generally accepted to result in an
improvement of the risk profile. Dietary improvement and increased
exercise are essential first steps and should continue even if drug
therapy is instituted, but the therapeutic potential of drug
therapy is significantly larger. Several types of drug therapy for
hypercholesterolaemia are currently available. Guidelines exist for
the treatment of hypercholesterolaemia for example, American Heart
Association (AHA) (Anon 1988), Updated Sheffield treatment tables
(Heart (1998) 80 Supp. 2 S1-S29) and Recommendations of the task
force of the European Society of Cardiology Guidelines (Pyorala
1994).
[0003] HMG-CoA reductase inhibitors are the most widely used
prescription medication for the treatment of hypercholesterolaemia.
By inhibiting the rate-controlling step in cholesterol
biosynthesis, these agents effectively lower the plasma
concentrations of atherogenic particles containing cholesterol such
as low-density lipoprotein (LDL-C) and very low-density lipoprotein
(VLDL-C). Partial inhibition of hepatic cholesterol synthesis
causes up-regulation of hepatic membrane LDL-C receptors which are
responsible for the clearance of LDL-C from the circulation. In
addition, reduced hepatic synthesis of cholesterol is thought to
result in a modest reduction in the secretion of VLDL-C particles
by the liver. Clinical trials with certain HMG Co A-reductase
inhibitors, such as in the Scandinavian Simvastatin Survival Study,
confirm a reduction in cardiovascular morbidity and mortality with
such agents, and may even promote regression of atherosclerotic
vascular lesions. Various HMG Co A-reductase inhibitors are
marketed, and are collectively referred to as `statins`.
[0004] Despite the impressive benefits of statin therapy, less than
optimal therapeutic results may be achieved in some subjects,
particularly in the more severe classes of hypercholesterolaemia.
This can be due to the occurrence of reversible increases in liver
transaminase levels at higher dose levels of statins as well as
differences in efficacy between different statins. Clinically
important (>3 times upper limit of normal [ULN]) elevations in
serum alanine aminotransferase [ALT]) have been reported for
atorvastatin in 0.8 percent of patients at low doses of
atorvastatin and higher at raised doses (European Summary of
Product Characteristics [SmPC] for atorvastatin [Lipitor.TM.]). In
all cases the effect is dose-related and reversible. In general it
is the incidence of ALT increases which limits dose escalation of
statins rather than a limit to further increases in efficacy.
[0005] The first generation statins (such as lovastatin,
pravastatin and simvastatin--prodrug derivatives of fungal
metabolites--and fluvastatin) are categorised in that they achieve
only a limited cholesterol lowering affect before the dose
administered is limited by elevations in serum ALT. Second
generation "superstatins" (such as atorvastatin--synthetic
compounds--structurally distinct from first generation compounds)
inhibitors are categorised in that they lower cholesterol levels to
a much higher degree than the earlier first generation of statins
before their dose is limited by serum ALT levels. Atorvastatin has
been successful over the first generation of statins. Since its
launch in the USA atorvastatin has reached sales in 1998, doubling
from 1997, of $2.2 billion, capturing 38% of new prescriptions for
cholesterol-lowering agents in the US and is now the most widely
prescribed hypolipidaemic agent in the US (Warner-Lambert 1998
annual results).
[0006] An additional adverse event, reported for statins in
general, is myopathy, defined as symptoms of muscle pain,
tenderness and weakness, with creatinine kinase (CK)
values>10.times.Upper Limit of Normal (ULN). This adverse event
is not considered to be dose related, and in addition the adverse
events are potentially more serious, and consequently more
problematical. In severe cases this can lead to rhabdomyolysis,
which is a rare life threatening condition sometimes associated
with renal failure. The incidence of raised CK levels
(>10.times.ULN-on 2 occasions at least 1 week apart with
symptoms=myositis according to FDA) for statins has been reported
as 3.1 percent. (SmPC for atorvastatin). Myopathy and
rhabdomyolysis have been particularly associated with taking a
statin in combination with gemfibrozil, niacin, cyclosporin or
erythromycin, (Hunninghake H. Et al. Current Opinion in Lipidolgy
(1992), 3, 22-28) which are all substrates for P450 isoenzyme 3A4.
The increase in adverse events associated with taking a combination
of a statin drug with one of the other drugs mentioned above is
probably due to a drug:drug interaction likely related to the
metabolism of most statins also by the same cytochrome P450
isoenzyme 3A4. Therefore when a drug which is also metabolised by
P450 3A4 is administered alongside a statin which also is
metabolised by P450 3A4, the side effects discussed above are more
likely to occur. Increase in the side effects, such as muscle
damage, is thought to be due to elevated statin levels in muscle
cells inhibiting farnesylation and geranylgeranylation of muscle
proteins. Elevated levels of statins may be caused by any drug
which affects P450 3A4. Therefore, currently on the labels of all
commercially available statins the use of the statin in combination
with drugs that are metabolised by P450 3A4 is not recommended and
is contraindicated in certain cases.
[0007] Nearly all drugs are metabolised to some degree in the
human, generally to a less lipid soluble compound which is more
easily excreted by the kidney or in liver bile. The liver is the
major site of drug metabolism and many drug metabolising enzymes
occur at high concentration in the endoplasmic reticulum (which
form microsomes upon homogenisation) of liver parenchymal cells
(hepatocytes). Cytochrome P450 represents a major class of drug
metabolising enzymes and exists as a family of isoenzymes found in
hepatic microsomes. Six specific P450 isoenzymes are responsible
for the metabolism of most of the commonly used drugs, namely P450
1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
[0008] A major disadvantage of the currently available "super
statin", atorvastatin, is that atorvastatin is metabolised by
cytochrome P450 enzymes, in particular 3A4, which may cause drug
interactions with other drugs which are inducers, inhibitors or
substrates of the same P450 enzyme which metabolises atorvastatin.
All of the first generation of statins are metabolised by P450
also. However, the rate of metabolism of pravastatin is
sufficiently low that it is considered less susceptible to
clinically relevant drug interactions. Therefore despite the lower
efficacy of pravastatin, in its currently available doses, at
reducing hypercholesterolaemia this is currently the statin of
choice in combination with other drugs where the possibility of
drug interactions is unacceptably high.
[0009]
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a
pharmaceutically acceptable salt thereof (the calcium salt of which
is disclosed in FIG. 1 below), hereinafter referred to as the
Agent, is also a statin and belongs to the class of what is now
starting to be called a "superstatin".
[0010] The Agent is disclosed in European Patent Application,
Publication No. 0521471, and in Bioorganic and Medicinal Chemistry,
(1997), 5(2), 437-444 as an inhibitor of HMG-CoA reductase which is
a major rate-limiting enzyme in cholesterol biosynthesis. The Agent
is described as useful in the treatment of hypercholesterolaemia,
hyperlipoproteinaemia and atherosclerosis.
[0011] The Agent is not metabolised by cytochrome P450 3A4 and
therefore does not possess the same potential for drug interaction
shared with the currently available "super statin", i.e.
atorvastatin, or any of the other currently available statins.
[0012] Therefore we present as a feature of the invention a
non-interacting drug combination comprising a HMG CoA reductase
inhibitor, which is the Agent, and a drug which is an inhibitor,
inducer or substrate of P450 in particular, isoenzyme 3A4.
[0013] As a further feature of the invention we present use of a
HMG CoA reductase inhibitor, which is the Agent, in the preparation
of a medicament for use in combination therapy with a drug which is
an inhibitor, inducer or substrate of P450, in particular,
isoenzyme 3A4.
[0014] As a further feature of the invention we present use of a
drug which is an inhibitor, inducer or substrate of P450, in
particular, isoenzyme 3A4 in the preparation of a medicament for
use in combination therapy with a HMG CoA reductase inhibitor,
which is the Agent.
[0015] As a further feature of the invention we present a
pharmaceutical formulation comprising the Agent, a drug which is an
inducer, inhibitor or substrate of P450 isoenzyme 3A4 and a
pharmaceutically-acceptable diluent, carrier or adjuvant.
[0016] As a further feature of the invention we present a pharmacy
pack comprising a first drug which is the Agent and a second drug
which is an inducer, inhibitor or substrate of P450 isoenzyme
4A4.
[0017] By the term "inducer of P450" we mean a drug which increases
the rate at which a P450 enzyme, in particular isoenzyme 3A4,
metabolises a substrate, for example by increasing the activity of
the P450 enzyme, decreasing the rate of biological inactivation of
the P450 enzyme or by increasing the rate of tanscription of the
P450 gene.
[0018] By the term "inhibitor of P450" we mean a drug which lowers
the rate at which a P450 enzyme, in particular isoenzyme 3A4,
metabolises a substrate, for example by lowering the activity of
the P450 enzyme or by lowering the rate of transcription of the
P450 gene.
[0019] By the term "substrate of P450" we mean a drug which is
metabolised by a P450 enzyme, in particular isoenzyme 3A4.
[0020] By the term "non-interacting drug combination" we mean a
drug combination for which there is no adverse affect to the
patient by its administration through the mechanism of drug
metabolism by cytochrome P450 isoenzyme 3A4. It is recognised that
in certain instances a drug interaction may nevertheless occur
between two such drugs when in combination through a completely
different mechanism not involving drug metabolism, such as
affecting drug absorption.
[0021] Whether a drug is an inhibitor, inducer or substrate of a
P450 enzyme can be easily determined by procedures known to the
skilled person. Such procedures may involve the exposure of a
radiolabelled drug to hepatocytes or hepatocyte microsomes or
isolated P450 enzyme and the use of analytic techniques, such as
HPLC, in determining metabolite formation. A specific procedure is
described herein.
[0022] By the term "combination" we mean either that the Agent and
the drug of the combination are administered together in the same
pharmaceutical formulation or that the Agent and the drug are
administered separately. When administered separately components of
the combination may be administered to the patient simultaneously
or sequentially.
[0023] We have found that the Agent is not metabolised
significantly by the major cytochrome P450 isoenzymes 1A2, 2C9,
2C19, 2D6 and 3A4. This is a further feature of the invention.
[0024] Preferred non-interacting combinations of the invention
include those in which the Agent is combined with a drug which is
also involved in lowering cholesterol and is also an inducer,
inhibitor or substrate of P450 3A4. Examples include fibrates, such
as bezafibrate, clofibrate, ciprofibrate, fenofibrate and
gemfibrizol (preferably fenofibrate), and niacin. Specific
embodiments of this preferred feature are described in Section B
below.
[0025] Preferred non-interacting combinations of the invention
include those in which the Agent is combined with a drug which is
involved in treating cardiovascular conditions and which is also an
inhibitor, inducer or substrate of P450 3A4. Examples include
digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil
and warfarin.
[0026] Preferred non-interacting combinations of the invention
include those in which the Agent is combined with cyclosporin
and/or tacrolimus (FK506) and therefore has utility in treating
elevated cholesterol levels in patients who are about to, or have
recently undergone, a transplantation operation. Specific
embodiments of this preferred feature are described below.
[0027] Preferred patients in which the combination of the invention
is to be administered are those who suffer from myopathy or
rhabdomylosis or who have already been found to suffer from
myopathy or rhabdomylosis when treated with HMG Co A reductase
inhibitor which is metabolised by P450 3A4, for example
atorvastatin, simvastatin and lovastatin.
[0028] Other features of the invention include those described
above wherein the Agent is used at doses of 5 to 80 mg per day.
When a dose range of 5 to 80 mg per day is referred to herein for
the Agent other particular dosage ranges, which are further
independent aspects of the invention, include (as appropriate) 10
to 80 mg per day, 10 to 60 mg per day, 10 to 40 mg per day, 5 to 40
mg per day, 5 to 20 mg per day, 10 to 20 mg per day, 20 to 60 mg
per day, 20 to 40 mg per day and 40 to 60 mg per day. Particular
dosages are 5, 10, 20, 40 and 80 mg per day. A particularly
suitable starting dose of the Agent in the methods referred herein
is 5 to 10 mg per day, especially 10 mg per day.
[0029] P450 3A4 substrates include; acetominophen, aldrin,
aflentanil, amiodorane, astemizole, benzphetamine, budenoside,
carbamazepine, cyclophosphamide, cyclosporin, dapsone, digitoxin,
ditiazem, diazepam, erthromycin, etoposide, flutamide,
hydroxyarginine, ifosphamide, imipramine, lansoprazole, lidocaine,
lovatidine, losartan, lovastatin, midrazolam, nifedipine,
omeprazole, quinidine, rapamycin, retenoic acid, steroids,
tacrolimus, teniposide, theophyline, toremifene, triazolam,
troleandomycin, verapamil, warfarin, zatosetron and zonisamide.
[0030] P450 3A4 inhibitors include; clotrimazole, ethinylestradiol,
gestodene, itraconazole, ketoconazole, miconazole, diltiazem,
naringenin, erthromycin, cyclosporin and triacetyloleandomycin.
[0031] P450 3A4 inducers include; carbamazepine, dexamethasone,
phenobarbital, phenyloin, rifampin, sulfadimidine, sulfinipyrazone
and triacetyloleandomycin.
[0032] Examples of other P450 inducers, inhibitors or substrates
include those mentioned in Drug Metabolism Reviews (1997) Vol 29,
Issue 1+2, pages 413-580, Rendic, S. and Di Carlo, F. J. "Human
cytochrome P450 enzymes,: A status report summarising their
reactions, substrates, inducers and inhibitors".
[0033] Dosages of the Agent may be administered according to the
cholesterol lowering effect desired from a range of 5 to 80 mg per
day in any number of unit dosages. Dosages of the drug which is an
inducer, inhibitor or substrate of P450 3A4 are those which are
advised for each drug, or which are commercially available.
Advantageously, due to the lack of interaction at the level of P450
3A4, the skilled person may dose the Agent with a drug which is an
inducer, inhibitor or substrate of P450 3A4 with out needing to
make any adjustments.
[0034] The dose ranges and dosages described above are further
independent features of the invention.
[0035] Preferably the Agent is
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt
(illustrated in FIG. 1).
EXPERIMENTAL
[0036] The experiment below is used to determine the in vitro
metabolic fate of [.sup.14C]-labelled Agent in human hepatocytes
and, in addition, to determine the specific P450 isozymes involved
in [.sup.14C]-labelled Agent metabolism, if any. The latter
experiment involves an investigation of the effects of P450
selective chemical inhibitors (see Table 1) on the metabolism of
[.sup.14C]-labelled Agent.
TABLE-US-00001 COMPOUND: [.sup.14C]-labelled Agent. Chemical name:
Bis [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-
dihydroxyhept-6-enoic acid] calcium salt Isomer: 3R,5S,6E
Stereoisomer Molecular weight: 1001.16 (Ca salt) Formulation
ingredients: The labelled Agent is dissolved in water to produce a
solution suitable for addition to the incubates. TISSUE SOURCE
Human liver, suitable for the preparation of microsomes and
hepatocytes, obtained from The International Institute for the
Advancement of Medicine (Exton, USA). Human hepatocytes may, in
addition, be obtained from Biowhittaker Ltd. or United Kingdom
Human Tissue Bank (Leicester, England).
Experimental Procedures
(1) Metabolism of [.sup.14C]-Labelled Agent by Human
Hepatocytes
[0037] [.sup.14C]-labelled Agent (1 .mu.M or higher concentration
if required for analytical sensitivity) was incubated with
hepatocytes in culture obtained from two human organ donors.
Cultures were terminated with ethanol after 0, 6, 24 and 48 hours
of incubation and stored at approximately -20.degree. C. until
analysed. The metabolic competence of the hepatocytes was confirmed
at the time of incubation by examining their ability to metabolise
[.sup.14C]-ethoxycoumarin (25 .mu.M); aliquots were removed into
methanol at the same time points as for the test compound.
[0038] Following incubation of [.sup.14C]-ZD4522 with hepatocytes,
metabolite profiles were generated by High Performance Liquid
Chromatography (HPLC). The ability of hepatocytes to metabolise
[.sup.14C]-ethoxycoumarin was confirmed by HPLC.
Assessment of Data
[0039] Data generated was assessed with regard to the
following:--
(1) Assess whether human hepatocytes metabolise [.sup.14C]-labelled
Agent. (2) Quantitate the amount of each metabolite formed.
(2) Enzymes Involved in Metabolism of the Agent
[0040] [.sup.14C]-labelled Agent (at an appropriate concentration)
was incubated with human hepatic microsomes in the absence and
presence of selective P450 inhibitors (see Table 1). Similar
incubations of [.sup.14C]-labelled Agent with individual
heterologously expressed P450 isoenzymes was also performed.
Incubations were terminated by the addition of an appropriate
organic solvent. Metabolite profiles of the incubates are generated
by HPLC.
TABLE-US-00002 TABLE 1 Selective chemical inhibitors of P450
isozymes P450 isozyme Selective inhibitor 1A2 Furafylline 2C9
Sulphaphenazole 2C19 Omeprazole 2D6 Quinidine 3A4 Ketoconazole
[0041] Assessment of Data
[0042] Data generated during this study was assessed with regard to
the following:-- [0043] (a) The rate and extent of metabolism of
[.sup.14C]-labelled Agent. [0044] (b) The ability of the selective
P450 inhibitors to decrease the metabolism of [.sup.14C]-labelled
Agent was compared in order to determine the isozyme(s) involved in
the metabolism of [.sup.14C]-labelled Agent. [0045] The ability of
individual expressed P450 isoforms to metabolise
[.sup.14C]-labelled Agent was assessed to aid determination of the
P450 isozyme(s) involved in the metabolism of [.sup.14C]-labelled
Agent. [0046] (c) These in vitro data can be used to predict the
variability of the pharmacokinetics of the Agent in the population
and the likely effects on the pharmacokinetics of the Agent during
co-administration with known P450 enzyme inhibitors/inducers.
[0047] It was found that the Agent was not significantly
metabolised by whole hepatocytes and that this was inhibited by
sulphaphenazole and omeprazole.
For Treating Hyperlipidaemia and Associated Conditions in Post
Transplant Patients Receiving Immunosuppressive Therapy.
[0048] Two common drugs used in suppressing the human immune
system, cyclosporin and tacrolimus (formerly called FK506), are
known to be metabolised by cytochrome P450 3A4. In particular
cyclosporin is also a known inhibitor of P450 3A4 and is therefore
likely to reduce the metabolism of any other drug which is
metabolised by P450 3A4.
[0049] Therefore where immunosuppressive therapy is prescribed,
such as with the drugs cyclosporin and tacrolimus (especially
cyclosporin), the attendant physician must be cautious as to any
other therapy which may be jointly presented to the patient in
combination. Immunosuppressive therapy is most commonly used
before, during and after human transplant operations. In particular
with cardiac transplants the attendant physician may wish to also
place the patient on statin drug therapy to reduce future incidents
of coronary heart disease, stroke, peripheral arterial occlusive
disease or peripheral vascular disease, particularly in patients
with elevated cholesterol or in normolipidaemic patients with other
risk factors associated with heart disease. In particular within
this special patient group (human transplant patients), the
patients are at high risk of developing accelerated atherosclerosis
in the transplant organ in an aggressive fashion and within a short
period of time due, in part, to the surgical damage to the blood
vessels during transplantation, any previously underlying untreated
conditions and the immunosuppressive therapy. Hyperlipidaemia is
common after transplantation even in patients who did not suffer
hyperlipidaemia prior to transplantation, incidence 60-80% of
recipients.
[0050] It is known that certain immunosuppressive drugs, such as
steroids, cyclosporin and tacrolimus, raise cholesterol levels in
patients (Wierzbicki A S (1999) IJCP 53 (1) 54-59). In addition
cyclosporin and tacrolimus may raise the levels of fibrinogen and
lipoprotein (a) in the patient, further accelerating the
progression of atherosclerosis in the transplant patient (Hohaye H,
Clin. Transplant (1997) 11, 225-230 and Hilbrands L B, J. Am. Soc.
Nephrol (1995) 5, 2073-2081). This unusually accelerated
atherosclerosis is present in about 20% of heart transplant
patients at 1 year and 40-65% at 5 years (Chang G. Et al. American
Heart Journal (1998), 136(2), 329-334). The incidence of
accelerated atherosclerosis has been reported as causing a 1-18%
incidence of CHD at one year and 20-50% incidence of CHD at 3 years
in cardiac transplant patients (Erdoes L S, J. Vasc. Surg. (1995)
22, 434-440). Lovastatin, pravastatin and simvastatin have all
shown to lower cholesterol levels in heart transplant patients. In
a placebo controlled study pravastatin increased survival of
transplant patients by 1 year and significantly reduced the
incidence of haemodynamic organ rejection. Because of the lower
incidence of serious drug interaction with the immunosuppressive
therapy pravastatin is currently the statin drug of choice in post
transplant treatment regimes. However, as discussed above,
pravastatin does not lower lipid/cholesterol levels to such a great
extent as, for example, atorvastatin.
[0051] We have discovered that the Agent is extremely effective at
treating hypercholesterolaemia in patients following
transplantation and that the Agent is not metabolised by cytochrome
P450 isoenzyme 3A4. Therefore we have found through the use of the
Agent in a clinical study that the Agent may be conveniently dosed
to patients who are undertaking immunosuppressive therapy without
any clinically significant side effects associated with the
concomitant dosing of the Agent and the immunosuppressive drug(s)
and, in addition, also achieve much higher levels of cholesterol
lowering than has previously been achieved, such as by the use of
pravastatin.
[0052] We present as the first feature of the invention a method of
providing safe non-interacting cholesterol lowering therapy to a
human patient undertaking immunosuppressive chemotherapy which
method comprises administering to the patient the Agent.
[0053] Particular patients undertaking immunosuppressive
chemotherapy who may benefit from the method of the invention are
those who: [0054] 1) suffer primary (type IIa)
hypercholesterolaemia (LDL-L.gtoreq.135 and TG<200); [0055] 2)
suffer combined (type IIb) hypercholesterolaemia (LDL-C.gtoreq.135
and TG.gtoreq.200); [0056] 3) patients with established CHD or
other atherosclerotic disease, such a PVD, stroke or peripheral
arterial occlusive disease; [0057] 4) patients who are at high risk
of developing CHD or other atherosclerotic disease, such as
described above, because of a combination of risk factors. The term
"high risk" is defined in the "Recommendations of Second Joint Task
Force of European and other Societies on Coronary Prevention",
(Wood, D. et. al. European Heart Journal, Atherosclerosis and
Journal of Hypertension 1998) as absolute CHD risk of .gtoreq.20%
over 10 years or will exceed 20% if projected to age 60 years.
Whether a patient is at high risk or not may be determined by the
charts which accompany the above recommendations and which charts
are incorporated herein by reference. For example a male patient in
his 40s who smokes and has a systolic blood pressure of 180 mm Hg
or higher and a total plasma cholesterol concentration of 7 mmol/L
or higher will be classified as high risk. Similarly other
guidelines for reducing risk factors may be applied such as those
described in; [0058] a) JAMA, Jun. 16, 1993--Vol 629, No. 23, Pages
3015-3023--"Summary of the NCEP Adult Treatment Panel II
Report"--specifically FIG. 1. Page 3018-3019 which is incorporated
herein by reference. [0059] b) Post Graduate Medical Journal 1993;
69(811): 359-369--"Management of hyperlipidaemia: guidelines of the
British Hyperlipidaemic Association"--specifically Table V and
Table VI which are incorporated herein by reference. [0060] c)
Heart 1998; 80 Supplement 2:S1-S29--"Joint British recommendations
on prevention of coronary heart disease in clinical
practice"--specifically FIG. 1 on pages S4-S5, which is
incorporated herein by reference. [0061] d) The Lancet 1995; Dec.
2, Vol. 346, 1467-1471--"Sheffield risk and treatment table for
cholesterol lowering for primary prevention of coronary heart
disease"--specifically the Table appearing at page 1468, which is
incorporated herein by reference. [0062] 5) patients who suffer
type I or II diabetes; [0063] 6) patients who are about to or have
already undertaken a heart transplant;
[0064] The statin therapy may be administered so as to achieve in
the patient undertaking immunosuppressive chemotherapy. [0065] 1) A
reduction in the internal thickness of coronary artery atheroma of
.gtoreq.30% as measured by IVUS. [0066] 2) A reduction of LDL-C of
at least 30, 40, 50%. [0067] 3) A maintenance or increase of HDL-C
of at least 5, 10, 15%. [0068] 4) A change in any of the above
values better than pravastatin at a similar dose and over the same
period.
[0069] As a further feature of the invention, and due also to the
fact that the Agent is not metabolised to any significant extent by
P450 isoenzymes, it is possible to administer, more safely than
before, to a patient receiving immunosuppressive therapy a fibrate
and the Agent. As discussed earlier the administration of a fibrate
and a statin has previously been associated with a higher incidence
of rhabdomyolysis and myopathy. In addition fibrate drugs do
interact with cyclosporin due to both being metabolised by the same
P450 isoenzyme. Therefore, the use of a statin and a fibrate drug
in combination with immunosuppressive therapy was previously
contraindicated due to the likelihood of possible serious
interactions (Hunninghake 1992, Wanner C. Kidney Int. (1995) 52
(suppl.), S60-S62; and Katznelson S. Contributions Nephrol. (1997)
120, 97-104). However, if possible, it would be advantageous to
also administer a fibrate alongside a statin since fibrates are
known to lower different lipoproteins than statins and therefore
their combined pharmacology would be complementary in reducing even
further the likelihood of CHD and other diseases mentioned above
associated with the formation of atherosclerosis. Therefore the
possibility of combining the Agent, which is not metabolised by
P450 3A4, with a fibrate and an immunosuppressive therapy offers
the additional possibility of lowering cholesterol to a greater
extent in such patients than previously achieved and more safely
than could previously be achieved by the administration of a
statin, a fibrate and an immunosuppressive drug.
[0070] Fibrate drugs are thought to act through peroxisomal
proliferating activator receptor-.alpha. (PPAR-.alpha.) and affect
gene activation at a number of genes involved in atheroma. Patients
on fibrate drugs show improved LDL subfraction distribution
(reduced VLDL and raised HDL), reduced LDL and reduced triglyceride
levels, and possible advantages through improving insulin
sensitivity. Examples of fibrate drugs include, bezafibrate,
ciprofibrate, fenofibrate and gemfibrozol.
[0071] By use of the term "safe non-interacting statin therapy" we
mean that the Agent is not metabolised by P450 3A4 and therefore
does not affect the metabolism of the immunosuppressive therapy or
vice versa.
[0072] Diseases and conditions in which immunosuppressive therapy
may be prescribed include, in addition to organ transplantation
mentioned above, autoimmune diseases, including rheumatic
disorders, such as, rheumatoid arthritis, osteoarthritis, lupus
erthematosus; and other autoimmune disorders such as idiopathic
thrombocytopenic purpura, autoimmune haemolytic anaemia and acute
glomerulonephritis.
[0073] The agent may be administered at the same time as the
immunosuppressive chemotherapy, or if not at the same time within a
short time period of administration of the immunosuppressive
therapy, such as in the same day, within 6, 3, 2 or 1 hour.
[0074] The Agent may be administered according to the cholesterol
lowering effect desired from a range of 5-80 mg per day in any
number of unit dosages, preferable once a day dosing. Ideal doses
are 10, 20 and 40 mg once per day. Preferred doses are 20 and 40 mg
once per day.
[0075] Particular immunosuppressive drugs which may be combined
with the Agents are those which are metabolised by liver enzymes,
such as by P450 3A4, and therefore are not likely to have a drug
interaction with the Agent. Examples include those described above,
cyclosporin and tacrolimus, as well as corticosteroids, which are
also metabolised in the liver. Examples of corticosteroids include
prednisone (especially used for organ transplantation). Preferably
at least one of the immunosuppressive agents, if more than one
agent is used, is either cyclosporin or tacrolimus, preferably
cyclosporin.
Example
[0076] The following non-limiting example is of a clinical trial to
demonstrate the performance of this aspect of the invention.
TABLE-US-00003 PROTOCOL Title: A Double-blind, Parallel Group Study
to Assess the Change in Coronary Artery Atheroma Burden Post
Cardiac Transplantation as Measured via IVUS after 12 Months Dosing
with the Agent versus Pravastatin Objectives: The primary objective
of the study is to measure change in maximal mean intimal thickness
of the anterior descending coronary artery as assessed by
intravascular ultrasonography (IVUS) (read centrally) after 12
months of treatment with the Agent or pravastatin. A change from
baseline of .gtoreq.30% in intimal thickness is considered
clinically significant. The secondary objectives of the study are
to measure the effects on coronary artery atheroma burden and to
compare effects of the Agent with the following assessments:
evidence of organ rejection as assessed by adverse event reports.
measurement of LDL-C, HDL-C, apoB, apoA-I, Lp (a) concentrations,
ex vivo platelet aggregation, fibrinogen, PAI-I, and the
concentrations of circulating markers of vascular inflammation.
comparison of lipid values after 52 weeks of treatment. measurement
of inflammatory markers after 52 weeks of treatment (HLA antigen
VCAM/ICAM expression as assessed by biopsy). to determine the
drug's safety and tolerability. Type and number of subjects:
Approximately 40 men and women (aged 18 years and older) post
cardiac transplant with hypercholesterolemia and triglycerides
<400 mg/dl at the time of randomisation. Trial treatment: Once
daily doses of the Agent (10 mg) or pravastatin (10 mg) for two
weeks, then titration of dose to 20 mg of the Agent or pravastatin
20 mg. After 4 weeks the dose should be titrated up to 40 mg of the
Agent or 40 mg pravastatin. Patients who have had their dose
titrated up to 40 mg may have their dose titrated down to 20 mg, at
the discretion of the investigator. Duration of treatment: Eligible
subjects randomised to 1 of 2 treatment groups, the Agent or
pravastatin, for 52 weeks. Primary measure: Mean change from
baseline in maximal mean intimal thickness, as assessed by IVUS
(read centrally). Secondary measures: Percent change from baseline
in LDL-C at 6 and 12 months. Percent change from baseline in total
cholesterol (TC), low-density lipoprotein cholesterol (LDL-C),
high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C,
TC/HDL-C, non-HDL-C/HDL-C, and triglycerides (TG). Percent change
from baseline in ApoB, ApoB/ApoA-1, ApoA-1, Lp (a), and particle
subfractions at 6 and 12 months. Percentage of subjects on each of
the possible titrated doses at 12 months. Endocardial rejection
will be considered an adverse event. Percent change from baseline
in inflammatory markers (HLA antigen level and ICAM/VCAM
expression). Safety evaluation as determined by adverse events,
physical examination, and laboratory data.
Trial Design
[0077] This is a multicenter, randomized, double-blind,
parallel-group clinical trial. Within 1 to 4 weeks post surgery,
subjects are randomized to receive either the Agent or pravastatin
for 52 weeks. Subjects start treatment at a dose of 10 mg of either
the Agent or pravastatin at Visit 2 and the dose is titrated to 20
mg at Visit 3 during the forced titration period. At Visit 4 and
subsequent visits, the investigator has the option to increase each
drug up to 40 mg during the optional titration period. Patients who
have had their dose titrated up to 40 mg may have their dose
titrated back down to 20 mg at the investigator's discretion.
TABLE-US-00004 TRIAL DESIGN Pre- Forced transplant Titration
Optional Titration Visit 1 2 3 4 5 6 7 8 9 10 11 Week (W)/ W0 W2 W4
M2 M3 M4 M5 M6 M9 M12 Month (M) Agent (mg) 10 20 .gtoreq.20*
PRAVASTATIN (mg) 10 20 .gtoreq.20* Randomisation** *Subjects who
are tolerating 20 mg of the Agent or Pravastatin at Visit 4 may
have their dose titrated up to 40 mg, at the discretion of the
investigator. **Subjects should be randomized within 4 weeks of
cardiac transplantation and must not have received any other lipid
lowering therapy post-surgery.
Inclusion Criteria
[0078] (1) have undergone cardiac transplantation up to four weeks
prior to randomization [0079] (2) fasting TG concentrations of
<4.52 mmol/L (400 mg/dl)
Exclusion Criteria
[0080] Any of the following is regarded as a criterion for
exclusion from the trial: [0081] (1) Use of other cholesterol
lowering drugs or lipid lowering dietary supplements or food
additives post-transplantation prior to entering the study [0082]
(2) history of serious or hypersensitivity reactions to other
HMG-CoA reductase inhibitors [0083] (3) pregnant women, women who
are breast feeding, and women of child bearing potential who are
not using chemical or mechanical contraception or have positive
serum pregnancy test (a serum .beta.-Human chorionic gonadotropin
[.beta.-HCG] analysis) [0084] (4) Subjects with a history of
diabetic ketoacidosis within the past 5 years are excluded. [0085]
(5) uncontrolled hypothyroidism defined as a thyroid stimulating
hormone (TSH)>1.5 times the ULN at Visit 2 or subjects whose
thyroid replacement therapy was initiated within the last three
months [0086] (6) use of concomitant medications as detailed
below--except immune suppressants and diazepam [0087] (7) current
alcohol and/or drug abuse [0088] (8) active liver disease or
hepatic dysfunction as defined by elevations of .gtoreq.1.5 times
the ULN at Visit 2 in any of the following liver function tests:
ALT, AST, or bilirubin [0089] (9) serum CK>3 times ULN at Visit
2 [0090] (10) serum creatinine>220 .mu.mol/L (2.5 mg/dl) [0091]
(11) subjects with cancer or with a history of cancer who, in the
opinion of the investigator, have more than a minimal chance of
recurrence [0092] (12) participation in another investigational
drug trial less than 4 weeks before randomization into the trial
[0093] (13) subjects randomized to double-blind treatment who
subsequently withdrew cannot re-enter this trial [0094] (14)
serious or unstable medical or psychological conditions that, in
the opinion of the investigator, would compromise the subject's
safety or successful participation in the trial [0095] (15)
subjects taking cyclic hormone replacement therapy (HRT), cyclic
oral contraceptive therapy (OCT), a depot progesterone injection,
or subjects whose non-cyclic HRT or OCT was initiated within the
last 3 months
Disallowed Medications
TABLE-US-00005 [0096] CLASS OF DRUG GENERIC NAME
Antibiotics/antifungals Erythromycin Base Erythromycin Ethyl
Succinate, Acetyl Sulfisoxazole Rifampicin Fluconazole Ketaconazole
Itraconzole Anti-epileptics/antidepressants Phenytoin Phenobarbitol
Fluoxetine Carbemazepine Acne treatment Isotretinoin Antiulcer
drugs Cimetidine Cisapride Systemic Steroids Triamcinolone
Acetonide Triamcinolone Diacetate Betamethasone Sodium Phosphate
Betamethasone Acetate Hydrocortisone Hydrocortisone Acetate
Hydrocortisone Sodium Phosphate Hydrocortisone Sodium Succinate
Cortisone Acetate Dexamethasone Dexamethasone Acetate Dexamethasone
Sodium Prednisone Methylprednisolone Methylprenisolone Acetate
Methylprednisolone Sodium Succinate Prednisolone Tebutate
Prednisolone Sodium Phosphate Methyltestosterone Fluoxymesterone
Antihistamine Astemizole Terfenadine Lipid Regulation
Niacin/Nicotinic Acid Probucol Psyllium Preparations Clofibrate
Cholestyramine Colestipol Hydrochloride Gemfibrozil Atorvastatin
Lovastatin Pravastatin (except study medication) Simvastatin
Fluvastatin Cerevestatin Fish oils (any dose) lipid lowering
dietary supplements lipid lowering food additives Hormone Therapy
Estrogen and progesterone combinations which are bi or tri
phasic.
Friedewald Equation
[0097] The LDL-C level is calculated from the Friedewald equation
as follows:
For SI Units (mmol/l)
LDL-C=Total cholesterol-[HDL-C+Triglycerides/2.2)
For Non-SI Units (mg/dl):
LDL-C=Total cholesterol-[HDL-C+triglycerides/5]
TABLE-US-00006 Summary of NCEP Goals for Lipid Management.sup.a
NCEP Risk Category Target LDL-C (NCEP) No CHD/PVD and 1 or no risk
factors <160 mg/dL No CHD/PVD and 2 or more risk factors <130
mg/dL Clinically evident CHD/PVD .ltoreq.100 mg/dL .sup.aSecond
Report of the Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults. Bethesda (MD): National
Institutes of Health, National Heart and Lung Institute 1993 Sep
Report No.: 93-3095. NCEP National Cholesterol Education
Program.
For Treating Hyperlipidaemia, and Associated Conditions, Using a
Combination of the Agent and a Fibrate Drug or Niacin
[0098] Myopathy and rhabdomyolysis have been associated with taking
a statin in combination with gemfibrozil, niacin, cyclosporin or
erythromycin, (HMG CoA reductase inhibitors, Hunninghake, Current
Opinion in Lipidology (1992) 3, 22-28) which are all substrates for
P450 3A4. Additionally, adverse events associated with taking a
fibrate drug have also been reported to increase with concomitant
statin therapy, such as a myosistis-flu like syndrome, which
occasionally occurs in patients receiving gemfibrozil, increases to
5% of patients when a statin is also administered.
[0099] Combination of a statin with a fibrate drug is
contraindicated on the labels, both in the USA and Europe, of all
commercially available statins. Despite the possibility of the
occurrence of serious drug interactions doctors do prescribe
combination therapy of a statin and a fibrate drug to patients with
more severe levels of hypercholesterolaemia, such as in patients
with familial combined hyperlipidaemia, where the risk of a serious
drug interaction is outweighed by the benefits of the combination
therapy. It is recommended that where combination therapy of a
fibrate drug and a statin is prescribed that patients should have
their CK value determined on a regular basis, typically every 6
weeks, until a stable pattern is established. Therapy is stopped if
muscle symptoms occur in association with elevated CK activity.
However, as quoted from the US label of Lipitor.TM. "there is no
assurance that such monitoring [of CK levels] will prevent the
occurrence of severe myopathy".
[0100] We have discovered that the Agent is extremely effective at
treating mixed hyperlipidaemia and hypertriglyceridaemia in
patients when combined with a fibrate drug and that the Agent is
not metabolised by cytochrome P450 isoenzyme 3A4. Therefore we have
found through the use of the Agent in a clinical study that the
Agent may be conveniently dosed to patients who are also taking a
fibrate drug without any clinically significant side effects
associated with the concomitant dosing of the Agent and the fibrate
drug. In addition much higher levels of lipid lowering than has
previously been achieved can be achieved by the use of the Agent
and a fibrate drug. The combination is of most use in mixed
hyperlipidemia where the LDL and VLDL and TGs are all elevated.
[0101] We present as the first feature of the invention a method of
providing safe non-interacting lipid lowering combination therapy
to a mammal, including a human patient, preferably a patient
suffering mixed hyperlipidaemia and hypertriglyceridaemia, which
method comprises administering to the patient the Agent and a
fibrate drug or niacin.
[0102] By the term "combination" as used herein we mean either (1)
that the Agent and the fibrate drug of the combination are
administered together in the same pharmaceutical formulation or (2)
that the Agent and the drug are administered separately. When
administered separately components of the combination may be
administered to the patient simultaneously or sequentially.
[0103] By the term "fibrate drug" we mean the class of drugs which
are based around the structure/activity of fibric acid and such
drugs include the following commercially available versions;
bezafibrate, clofibrate, ciprofibrate, fenofibrate and gemfibrizol
preferably fenofibrate.
[0104] Preferred patients in which the combination of the invention
is to be administered are those who have already been found to
suffer from myopathy or rhabdomylosis when treated with a statin
and/or with a fibrate drug which is metabolised by P450 3A4.
[0105] Particular patients who may benefit from the method of the
invention are those who:
1) suffer combined (type IIb) hypercholesterolaemia (typically
LDL-C.gtoreq.135 mg/dL and TG.gtoreq.200 mg/dL); 2) suffer familial
(type IV and V) hypercholesterolaemia; 3) patients suffering
secondary hypercholesterolaemia from such conditions as: [0106] a)
diabetes (type I or II), [0107] b) nephrotic syndrome, [0108] c)
uremia, [0109] d) hyperthyroidism, and [0110] e) obstructive liver
disease. 4) patients with established CHD or other atherosclerotic
disease, such a PVD, stroke or peripheral arterial occlusive
disease; 5) patients who are at high risk of developing CHD or
other atherosclerotic disease, such as described above, because of
a combination of risk factors. The term "high risk" is defined in
the "Recommendations of Second Joint Task Force of European and
other Societies on Coronary Prevention", (Wood, D. et. al. European
Heart Journal, Atherosclerosis and Journal of Hypertension 1998) as
absolute CHD risk of .gtoreq.20% over 10 years or will exceed 20%
if projected to age 60 years. Whether a patient is at high risk or
not may be determined by the charts which accompany the above
recommendations and which charts are incorporated herein by
reference. For example a male patient in his 40s who smokes and has
a systolic blood pressure of 180 mm Hg or higher and a total plasma
cholesterol concentration of 7 mmol/L or higher will be classified
as high risk. Similarly other guidelines for reducing risk factors
may be applied such as those described in; [0111] a) JAMA, Jun. 16,
1993--Vol 629, No. 23, Pages 3015-3023--"Summary of the NCEP Adult
Treatment Panel II Report"--specifically FIG. 1. Page 3018-3019,
which is incorporated herein by reference. [0112] b) Post Graduate
Medical Journal 1993; 69(811): 359-369--"Management of
hyperlipidaemia: guidelines of the British Hyperlipidaemic
Association"--specifically Table V and Table VI, which are
incorporated herein by reference. [0113] c) Heart 1998; 80
Supplement 2:S1-S29--"Joint British recommendations on prevention
of coronary heart disease in clinical practice"--specifically FIG.
1 on pages S4-S5, which is incorporated herein by reference. [0114]
d) The Lancet 1995; Dec. 2, Vol. 346, 1467-1471--"Sheffield risk
and treatment table for cholesterol lowering for primary prevention
of coronary heart disease"--specifically the Table appearing at
page 1468, which is incorporated herein by reference.
[0115] The statin therapy may be administered so as to achieve in
the patient receiving a fibrate drug or niacin: [0116] 1) a
reduction of LDL-C of at least 30, 40, 50, 60, 70 or 80%. [0117] 2)
a maintenance or increase of HDL-C of at least 5, 10, 15%. [0118]
3) a reduction in triglycerides of at least 10, 20, 30 or 40%.
[0119] The combination of the fibrate, or niacin, and the Agent may
be applied as separate dosage forms, which may be taken
simultaneously or sequentially, or in a combined dosage form. The
combination of the fibrate and the Agent will also have an additive
or synergistic effect on the reduction in LDL-C, maintenance or
increase of HDL-C or reduction in triglyceride in the patients
blood.
[0120] In addition the combination of niacin and the Agent may be
applied as separate dosage forms, which may be taken simultaneously
or sequentially, or in a combined dosage form. The combination of
the fibrate and the Agent will also have an additive or synergistic
effect on the reduction in LDL-C, maintenance 6r increase of HDL-C
or reduction in triglyceride in the patients blood.
[0121] Doses of the Agent which are administered are at the
discretion of the attendant physician generally taking into account
the severity of the disease, the age, weight and sex of the
patient. However typical doses will be from 5 to 80 mg per day
orally, preferably as a once a day oral tablet form.
[0122] Doses of the fibrate drug or niacin which are administered
in the combination of the invention also are at the discretion of
the attendant physician taking into account all of the above
factors plus in particular which drug is used.
[0123] For clofibrate (such as Atromid-S.RTM.) 20-30 mg/kg body
weight daily in 2 or 3 divided oral doses after meals is
typical.
[0124] For bezofibrate (such as Bezalip.RTM.) 400 mg once a day
orally, after food at night or in the morning, is typical.
[0125] For fenofibrate (such as Lipantil.RTM.) 200 mg once a day,
or 62 mg three times a day, with food is typical.
[0126] For gemfibrozil (such as Lopid.RTM.) 600 mg twice a day
orally is typical.
[0127] For cipofibrate (such as Modalim.RTM.) 100 mg once a day
orally is typical.
[0128] For niacin (NIASPAN.RTM., an extended release niacin
formulation, and preferred feature) 500 mg once to four times
daily, preferably twice or four times daily.
[0129] A preferred fibrate drug is fenofibrate.
[0130] Preferably the AGENT is administered to a patient receiving
niacin at 10 mg or 40 mg daily doses.
[0131] The particular aspect of this invention is illustrated by
the following non-limiting examples:
Clinical Trial
[0132] A Randomised, Non-controlled, Single-centre, Open-label,
3-way Crossover Trial to Assess the Effect of Co-administration of
the Agent and Fenofibrate on the Pharmacokinetics of Each Compound
in Healthy Male Volunteers
TABLE-US-00007 Objectives: The primary objective of this trial is
to assess the effect of co- administration of the Agent and
fenofibrate on the pharmacokinetics of both the Agent and
fenofibrate Type and number of The safety of all volunteers will be
ensured by clinical monitoring volunteers: 14 healthy male
volunteers Trial design: The trial will be a randomised,
non-controlled, 3-way crossover study carried out at a single
centre Trial treatment: This trial will consist of three 7-day
treatment periods (Periods A, B, and C). Volunteers will receive,
in random order, a 10 mg capsule of the Agent once daily for 7
days, a 67 mg fenofibrate capsule 3 times daily for 7 days and the
combination for 7 days. There will be a minimum of a 3-week washout
between each trial period. Duration of The study will consist of 3
periods of 7-day dosing (a total of 21 treatment: dosing days) with
a 3-week washout between dosing in Periods A, B and C. Primary
endpoints: The primary endpoints are: AUC(0-24) and C.sub.max of
the Agent in the presence and absence of fenofibrate AUC(0-8) and
C.sub.max of fenofibrate in the presence and absence of the Agent
Secondary the secondary endpoints are: endpoints: t.sub.max,
t.sub.1/2, C.sub.min for the Agent in the presence and absence of
fenofibrate t.sub.max, t.sub.1/2, C.sub.min for fenofibrate in the
presence and absence of the Agent safety assessments: symptoms,
blood pressure and pulse rate, ECG, clinical chemistry, haematology
and urinalysis
Trial Plan
Summary of Procedures
Overall Plan for Trial Periods A, B and C
TABLE-US-00008 [0133] Doses of the Agent/ fenofibrate or 12 lead
Safety Blood Kinetics of Kinetics Trial Days Medical combination P
& BP ECG & Urine the Agent Fenofibrate Pre-trial + + +
+.sup.a -1 +.sup.b 1 + +.sup.c +.sup.c 2 + +.sup.b +.sup.d +.sup.e
3 + +.sup.d +.sup.e 4 + +.sup.b 5 + 6 + +.sup.b +.sup.d +.sup.e 7 +
+ + +.sup.d +.sup.e 8 +.sup.b +.sup.d 9 +.sup.d 10 +.sup.b +.sup.d
Post-trial + + + +.sup.a +.sup.d .sup.aFull clinical chemistry,
haematology and urine labstix. .sup.bClinical chemistry only: urea,
creatinine, total protein, albumin, uric acid, total bilirubin (and
unconjugated and conjugated bilirubin if total bilirubin raised),
alkaline phosphatase, alanine aminotransferase (ALT), aspartate
aminotranseferase (AST), gamma glutamyltransferase, creatine kinase
(CK), sodium, potassium, calcium, cholesterol and triglycerides.
.sup.cPre-dose all trial periods. .sup.dOnly trial periods when
volunteers receive the Agent .sup.eonly trial periods when
volunteers receive fenofibrate P = pulse; BP = blood pressure
Trial Plan II
Trial Day 7 in Periods A, B and C
TABLE-US-00009 [0134] 12 Safety Kinetics P & lead blood &
of the Kinetics Meals & Time BP (L) ECG urine.sup.c Agent.sup.b
fenofibrate.sup.c Fluids Pre-dose + + + + B Dose (0 h) D 0.5 h + +
1 h + + 2 h + + D 3 h + + + + 4 h + + M, F 5 h + + + + 6 h + + 8 h
+ + S 10 h + M 12 h + + + F 14 h S 18 h + W 24 h + + +.sup.a + 30 h
+ 48 h + 54 h + 72 h +.sup.a + .sup.aclinical chemistry only: urea,
creatinine, total protein, albumin, uric acid, total bilirubin (and
unconjugated and conjugated bilirubin if total bilirubin raised),
alkaline phosphatase, ALT, AST, gamma glutamyltransferse, CK,
sodium, potassium, calcium, cholesterol and triglycerides.
.sup.bOnly trial periods when volunteers receive the Agent
.sup.cOnly trial periods when volunteers receive fenofibrate L =
lying; P = pulse; BP = blood pressure; D = drink; S = snack; M =
meal; F = free access to permitted fluid and food; W = free access
to water only
1 OBJECTIVES
Primary Objective
[0135] The primary objective of this trial is to assess the effect
of co-administration of the Agent and fenofibrate on the
pharmacokinetics of both the Agent and fenofibrate.
Secondary Objective
[0136] There is no secondary objective for this trial.
[0137] The safety of all volunteers will be ensured by clinical
monitoring.
Design
[0138] The trial will be a randomised, non-controlled, open-label,
3-way crossover study carried out at a single centre.
[0139] Volunteers will receive 3 treatment regimens in random
order: [0140] 10 mg of the Agent once daily for 7 days [0141]
fenofibrate (Lipantil.TM.) 67 mg.times.3 daily for 7 days [0142]
the Agent (10 mg once daily) and fenofibrate (Lipantil.TM., 67
mg.times.3 daily) given in combination for 7 days
[0143] There will be a minimum of 3 weeks (21 days) washout between
each treatment period.
Inclusion Criteria
[0144] For inclusion in the trial, volunteers must meet all of the
following criteria: [0145] male, aged between 18 and 65 years
inclusive [0146] normal clinical examination, including medical
history, resting electrocardiogram (ECG) and 24 hour continuous
ambulatory ECG (if not performed in the past 12 months) [0147]
negative screens for serum hepatitis B surface antigen and
hepatitis C antibody and a normal screen for ferritin within the
previous 12 months [0148] weight not differing by more than 20%
from the desirable weight (Metropolitan Height and Weight
Tables)
Exclusion Criteria
[0149] Volunteers must be excluded from the trial if any of the
following criteria are met: [0150] use of any medication or
therapy, including drugs of abuse [0151] receipt of another new
chemical entity in the 4 months before dosing in this trial (a new
chemical entity is defined as a compound which has not been
submitted for marketing authorisation) [0152] participation in
another trial within 3 months before the start of the present
trial, apart from non-invasive methodology trials in which no drugs
were given [0153] any acute illness within 2 weeks before the start
of the trial [0154] any clinically significant abnormalities in
clinical chemistry, haematology or urinalysis results. In addition
the following clinical chemistry parameters should be no greater
than the upper limit of normal: total bilirubin, ALT, AST and CK
[0155] risk (in the investigator's opinion) of transmitting,
through blood or other body fluids, the agents responsible for
acquired immune deficiency syndrome (AIDS), hepatitis B or
hepatitis C [0156] definite or suspected personal history or family
history of adverse drug reactions, or hypersensitivity to drugs
with a similar chemical structure to the Agent or related statins,
or fenofibrate and related fibrate drugs [0157] history or presence
of gastrointestinal, hepatic, biliary or renal disease or other
condition known to interfere with absorption, distribution,
metabolism or excretion of drugs [0158] history of Gilbert's
syndrome [0159] if participation in the trial would result in the
volunteer donating more than 1350 ml of blood in the 12 months
before the end of the trial [0160] excessive intake of alcohol,
defined as a maximum weekly intake of greater than 28 units (1 unit
equals half a pint of beer or a measure of spirits) [0161]
treatment in the previous 3 months with any drug known to have a
well-defined potential for hepatotoxicity (eg, halothane) [0162]
clinical judgement by the investigator or the volunteer's general
practitioner that the volunteer should not participate in the
trial
Volunteer Restrictions
[0163] Volunteers will be required to: [0164] abstain from taking
any medication (including over-the-counter remedies) from 96 hours
before Trial Day 1 to 72 hours after receiving the last dose of the
Agent or morning dose of fenofibrate in each trial period unless
the investigator has given prior consent [0165] fast from midnight
on the night before each trial day and eat a light breakfast on
arrival on Trial Day 1 to 7 in each trial period [0166] refrain
from driving, cycling, using machinery (drills, sanders, sharp
instruments etc.) for 24 hours after receiving first dose on Trial
Day 7 in each period [0167] remain for 24 hours after receiving
first dose on Trial Day 7 in each trial period [0168] abstain from
smoking, consuming grapefruit, grapefruit juice, liquorice or
caffeine-containing drinks or foods (eg, coffee, tea, cocoa,
chocolate and cola) from midnight before Trial Day 1 until 72 hours
after receiving the last dose of the Agent or morning dose of
fenofibrate in each trial period [0169] abstain from drinking
alcohol from 96 hours before Trial Day 1 until 72 hours after
receiving the last dose of the Agent or morning dose fenofibrate in
each trial period [0170] refrain from physical exercise from 96
hours before Trial Day 1 until 72 hours after receiving the last of
the Agent or morning dose of fenofibrate in each trial period
[0171] refrain from potentially hazardous work or activities, from
receiving the first dose of the Agent or fenofibrate until the
post-trial medical [0172] abstain from donating blood during the
trial and for 3 months following their last dose of trial
treatment
Formulation, Presentation and Storage
Dosage and Administration
[0173] Capsules of the Agent or fenofibrate will be taken orally
with 200 ml of purified water with the volunteer sitting in an
upright position.
[0174] On Trial Days 1 to 7 of each treatment period, volunteers
will receive one of the following treatments: [0175] 1.times.10 mg
capsule of the Agent to be taken between 08:30 and 09:30 hours
[0176] 3.times.67 mg fenofibrate capsules [0177] the 1st capsule to
be taken between 08:30 and 09:30 hours [0178] the 2.sup.nd capsule
to be taken between 16:30 and 17:30 hours with food [0179] the
3.sup.rd capsule to be taken between 22:30 and 23:30 hours with
food [0180] 1.times.10 mg capsule of the Agent and 3.times.67 mg
fenofibrate capsules: [0181] 1 capsule of the Agent and the
1.sup.st fenofibrate capsule to be taken simultaneously between
08:30 and 09:30 hours [0182] the 2.sup.nd fenofibrate capsule to be
taken between 16:30 and 17:30 hours with food [0183] the 3.sup.rd
fenofibrate capsule to be taken between 22:30 and 23:30 hours with
food
[0184] On Trial Days 1 to 6 of each trial period, volunteers will
visit the unit daily and will be allowed to leave the unit
immediately after administration of doses of the Agent, fenofibrate
or the Agent/fenofibrate combination, except on Trial Day 7 when
volunteers will remain resident for 24 hours.
[0185] In trial periods when the volunteers are randomised to
fenofibrate, they will take the further 2 doses of fenofibrate at
home. The volunteers will be provided with 1 pot of fenofibrate to
be taken as outlined above. Volunteers will be issued with a
pre-set timer to ensure that the dose is taken at the correct time,
and a diary card to document the dose was taken.
[0186] When the Agent and fenofibrate are given to the volunteers,
the tear-off labels will be attached to the appropriate case report
form (CRF). The investigator must ensure that each volunteer
receives the correct treatment.
Clinical and Laboratory Assessments
Primary Endpoints
[0187] The following parameters will be measured as primary
endpoints: [0188] AUC(0-24) and C.sub.max of the Agent in the
presence and absence of fenofibrate [0189] AUC(0-8) and C.sub.max
of fenofibrate in the presence and absence of the Agent
Secondary Endpoints
[0190] The following parameters will be measured as secondary
endpoints: [0191] t.sub.max, t.sub.1/2, C.sub.min for the Agent in
the presence and absence of fenofibrate [0192] t.sub.max,
t.sub.1/2, and C.sub.min for fenofibrate in the presence and
absence of the Agent safety assessments: symptoms, blood pressure
and pulse rate, ECG, clinical chemistry, haematology and
urinalysis.
Pharmaceutical Compositions
[0193] The following Example illustrates, but is not intended to
limit, pharmaceutical dosage forms which are suitable for use in
the invention as defined herein:
TABLE-US-00010 Capsule mg The Agent 5.0 Lactose 42.5 Cornstarch
20.0 Microcrystalline cellulose 32.0 Pregelatinised starch 3.3
Hydrotalcite 1.1 magnesium stearate 1.1
[0194] Capsules containing 1, 2.5 or 10 mg of the Agent may be
obtained similarly using more or less lactose as appropriate, to
maintain a total fill weight of 105 mg.
Abbreviations and Conventions Used
TABLE-US-00011 [0195] Abbreviation Term ALT alanine
aminotransferase ALP alkaline phosphatase apo B apolipoprotein B
100 AST aspartate aminotransferase AUC area under the concentration
curve from zero to infinity AUC(0-t) area under the curve of plasma
concentration against time from zero to time of last quantifiable
concentration CABG Coronary artery bypass graft C.sub.max maximum
concentration CK creatinine kinase CVA cerebrovascular accident ECG
electrocardiogram EAS European Atherosclerosis Society EDTA
ethylenediamine-tetraacetic acid XGT Gemma glutaryl transferase
HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A HDL high-density
lipoprotein HPLC high-performance liquid chromatography HRT hormone
replacement therapy IU International Units IVUS Intravascular
ultrasenography LDL low density lipoprotein LDL-C low density
lipoprotein cholesterol MVA mevalonic acid NC not calculable NCEP
national cholesterol eduction program NDSR national data system for
research THC tetrahydrocannabinol TG triglyceride t.sub.1/2
terminal elimination half-life t.sub.max time of maximum
concentration TC total cholesterol TG triglycerides TIA transient
ischemic attack TSH thyroid stimulating hormone ULN upper limit of
normal VLDL very low-density lipoprotein
* * * * *