SK287795B6 - Drug combinations comprising (E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid and an inhibitor, inducer or substrate of P450 isoenzyme 3A4 - Google Patents

Abstract

Non-interacting drug combinations include a 3-hydroxy -3- methylglutaryl coenzyme A reductase inhibitor, which is (E)-7- [4-(4-fluorophenyl) -6- isopropyl -2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R,5S)-3,5- dihydroxyhept -6-enoic acid or a pharmaceutically acceptable salt thereof and a drug which is either an inducer, inhibitor or a substrate of cytochrome P450, in particular cytochrome P450 isoenzyme 3A4. The combinations according to the invention are useful in treating hyperlipidaemia in humans who are receiving immunosuppressive chemotherapy.

Description

Technical field

The present invention relates to a safe, non-interacting combination of drugs, namely a 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor that is (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2] acid. - [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof (Agent), and a drug which is an inducer, inhibitor or substrate of cytochrome P450 isoenzyme 3A4. Such combinations are useful in the treatment of hyperlipidemia in humans undergoing immunosuppressive chemotherapy. A preferred combination is a combination of an agent and a fibrate type medicament for use in the treatment of hyperlipidemia in mammals, and a medicament comprising such a combination for use in such treatment.

BACKGROUND OF THE INVENTION

Hypercholesterolemia is one of the most important risk factors for arteriosclerosis associated with coronary artery disease (such as angina pectoris, myocardial infarction, and death), and stroke (such as cerebrovascular episode and transient ischemic episode), and occlusive peripheral disease. There are several types of hypercholesterolemia. Therapy depends on the extent of hypercholesterolemia, but generally, any reduction in elevated plasma cholesterol results in an improved risk profile. Diet change and increased physical activity are necessary first steps and should continue even after drug therapy is initiated, but the therapeutic potential of pharmacotherapy is significantly greater. Several types of drugs are currently available for hypercholesterolaemia. There are also various instructions for treating hypercholesterolemia, e.g. the instructions of the American Heart Association (AHA) (Anon 1988), Updated Sheffield Treatment Tables (Heart (1998) 80 Supp.2 S1-S29) and Recomendations of the Task Force of the European Society of Cardiology Guidelines (Pyorala 1994).

HMG-CoA reductase inhibitors are the most commonly prescribed medicine for the treatment of hypercholesterolemia. By inhibiting the cholesterol biosynthesis step that controls the rate of biosynthesis, these agents effectively reduce the concentration of atherogenic cholesterol-containing particles in plasma, such as low-density lipoprotein (LDL-C) and very low density lipoprotein (VLDL). (Very low-density lipoprotein). Partial inhibition of hepatic cholesterol synthesis causes activation of the hepatic LDL-C receptors, which are responsible for removing LDL-C from the circulation. In addition, reduced hepatic cholesterol synthesis results in a slight reduction in hepatic secretion of VLDL-C particles. Clinical trials with some HMG-CoA reductase inhibitors, such as e.g. the Swedish Scandinavian Simvastin Survival Study confirm that the use of such agents leads to a reduction in cardiovascular morbidity, and may even promote regression of atherosclerotic vascular lesions. Various HMG-CoA reductase inhibitors are available on the market, collectively referred to herein as "statins".

Despite the very impressive benefit of statin therapy, significantly worse results are achieved in some patients, especially in the most severe classes of hypercholesterolemia. This may be due to a reversible increase in liver transaminases at high doses of statins, as well as differences in the efficacy of different statins. A clinically significant increase (> 3x upper limit of normal, [UNL]) of alanine aminotransferase [ALT] in serum has been reported for atorvastatin in 0.8% of patients at low doses of atorvastatin and even higher at elevated doses (see “European Summary of Products Characteristics [SmPC”) ] ”For atorvastatin [Lipitor ™]). In any case, the effect is dose-dependent and reversible. In general, increasing the dose of statins is more limited by the occurrence of increased ALT than by limiting further increases in efficacy.

First-generation statins (such as lovastatin, pravastatin and simvastatin - prodrug derivatives of fungal metabolites, and fluvastatin) are categorized as having only limited cholesterol lowering before the dose is limited by increasing serum ALT. Second-generation inhibitors, "superstatins" (such as atorvastatin - a synthetic compound structurally different from first-generation statins), are categorized as lowering cholesterol levels to a much greater degree than first-generation, until the dose is limited by increasing serum ALT. Atorvastatin was more successful than first generation statins. After marketing in the United States, sales of $ 2.2 billion in 1998, doubling over 1997, accounted for 38% of the newly prescribed cholesterol-lowering drugs in the US, which is also the most widespread prescribed hypolipaemic drug (Warner- Lambert 1998).

An undesirable side effect described generally for statins is myopathy, defined by symptoms such as pain, tenderness, and muscle weakness with a creatinine kinase (CK) value greater than 10 times the upper limit of normal (ULN). These adverse side effects are believed to be dose independent and, in addition, are potentially more severe and their consequences more problematic. In some cases, they can lead to rhabdomyolysis, a life-threatening disease, sometimes associated with kidney failure. The incidence of elevated CK levels (> 10x ULN - occurrence twice by FDA at least 1 week with symptoms = myositis) for statins has been reported in 3.1% (see atorvastatin SmPC). In particular, myopathy and rhabdomyolysis have been associated with the use of statins in combination with gemfibrozil, niacin, cyclosporin or erythromycin (Hunnin2 ghake H. et al. Current Opinion in Lipidology (1992), 3, 22-28), all of which are substrates of the P450 isoenzyme 3A4. The potentiation of the adverse side effects associated with the use of a combination of a statin drug with one of said drugs is probably due to drug interaction, possibly related to the same 3A4 cytochrome P450 isoenzyme involved in the metabolism of most statins. Thus, when a drug metabolized by P450 3A4 is administered concomitantly with a statin that is also metabolized by P450 3A4, the side effects described herein are more likely to occur. The potentiation of side effects, such as muscle damage, is probably due to an elevated level of statin in muscle cells that inhibits famezylation and geranylgeranylation of muscle proteins. Elevated levels of statins may be caused by any drug acting on P450 3A4. Currently, the label and package leaflet of all commercially available statins state that their combination with drugs that are metabolised by P450 3A4 is not recommended and in some cases is even contraindicated.

Almost all drugs in the human body are metabolised to some extent, generally to less lipid soluble compounds, which are more readily secreted in the kidney or into the bile in the liver. The liver is the major organ where drugs are metabolized, and there are many drug metabolizing enzymes in high concentrations in the endoplasmic reticulum (which forms after microsomal homogenization) of the parenchymal liver cells (hepatocytes). Cytochrome P450 is a major class of drug metabolizing enzymes and exists as a family of isoenzymes found in liver microsomes. Six specific P450 isoenzymes, namely P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4, are responsible for the metabolism of most conventional drugs.

The major drawback of the currently available 'superstatin' atorvastatin is that it is metabolised by cytochrome P450 enzymes, namely 3A4, which may cause interactions with other drugs that are inducers, inhibitors or substrates of the same atorvastatin metabolizing enzyme. All first generation statins are also metabolized by P450. However, the metabolic rate of pravastatin is sufficiently low to be considered less susceptible to clinically significant drug interactions. Thus, despite the lower efficacy in the dosage currently available, pravastatin hypercholesterolaemia is the drug of choice in combination with other drugs where the possibility of drug interaction is unacceptably high.

(E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof (a calcium salt as shown in Fig. 1), hereinafter abbreviated as Agents, is also a statin and belongs to a class which has been called "superstatins".

The agent was first described in European patent application 0521471, as well as in a scientific publication (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 has been described as useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The agent is not metabolised by cytochrome P450 3A4 and therefore does not present the same potential risk for drug interaction as other currently available "superstatins", e.g. atorvastatin, or any of the other commonly available statins.

SUMMARY OF THE INVENTION

The present invention discloses non-interacting drug combinations comprising an HMG-CoA reductase inhibitor, which is an Agent, and a drug that is an inhibitor, inducer or substrate of P450, particularly the 3A4 isoenzyme.

Another aspect of the present invention is the use of an HMG-CoA reductase inhibitor, which is an Agent, for the manufacture of a medicament for use in combination therapy with a drug that is an inhibitor, inducer or substrate of P450, particularly the 3A4 isoenzyme.

Another aspect of the present invention is the use of a medicament that is an inhibitor, inducer or substrate of P450, in particular isoenzyme 3A4, for the manufacture of a medicament for use in combination therapy with an HMG-CoA reductase inhibitor which is an Agent.

Another aspect of the present invention is a pharmaceutical composition comprising an Agent, a medicament that is an inhibitor, inducer or substrate of the P450 isoenzyme 3A4 and a pharmaceutically acceptable diluent, carrier or adjuvant.

Another aspect of the present invention is a drug kit comprising a first drug which is an Agent and a second drug which is an inhibitor, inducer or substrate of P450, in particular the 3A4 isoenzyme.

The term "P450 inducer" according to the invention means a drug which increases the rate at which the P450 enzyme, in particular the 3A4 isoenzyme, metabolizes a substrate, e.g. by increasing the activity of the P450 enzyme, reducing the rate of biological inactivation of the P450 enzyme, or increasing the rate of transcription of the P450 gene.

The term "P450 inhibitor" according to the invention means a drug that reduces the rate at which the P450 enzyme, especially the isoenzyme 3A4, metabolizes a substrate, e.g. by decreasing the enzyme activity or decreasing the transcription rate of the P450 enzyme gene.

The term "substrate P450" according to the invention means a drug that is metabolized by the enzyme P450, especially the isoenzyme 3A4.

The term "non-interacting drug combination" according to the invention means a drug combination which, when administered, does not have a deleterious effect on the patient due to the metabolism of the drug by the cytochrome P450 isoenzyme 3A4. It is recognized, however, that in some cases, drug interaction in combination may occur, but with a completely different mechanism that does not involve drug metabolism, but e.g. drug absorption.

Whether a drug is an inhibitor, inducer or substrate of the P450 enzyme can be readily determined by a method known to those skilled in the art. The procedure consists in applying the radiolabeled drug to hepatocytes or hepatocyte microsomes or the isolated P450 enzyme and then using an analytical method such as HPLC to determine the formation of metabolites. A specific procedure is described in the present application.

The term "combination" according to the invention means either that the Agents and the drug combined therewith are administered together in the same pharmaceutical composition, or that the Agents and the drug are administered separately. When administered separately, they may be administered simultaneously or sequentially.

The Agent was found not to be significantly metabolised by most of the cytochrome P450 isoenzymes 1A2, 2C9, 209, 2D6 and 3A4. This is a further feature of the invention.

Preferred non-interacting combinations of the invention include an agent-containing combination in combination with a drug that is also involved in lowering cholesterol and is also an inducer, inhibitor or substrate of P450 3A4. Examples include fibrates such as e.g. bezafibrate, clofibrate, ciprofibrate, fenofibrate, gemfibrozil (preferably fenofibrate) and niacin. Specific preferred embodiments of the invention are described below.

Preferred non-interacting combinations of the invention include an agent-containing combination in combination with a medicament that is used to treat cardiovascular diseases and is also an inducer, inhibitor or substrate of P450 3A4. Examples include digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil and warfarin.

Preferred non-interacting combinations of the invention include an agent-containing combination in combination with cyclosporine and / or the tacrolimus drug (FK506) and is therefore useful for treating elevated cholesterol levels in patients who are currently preparing for or have undergone transplantation. Specific preferred embodiments of the invention are described below.

Patients receiving the combination of the invention preferably include patients suffering from myopathy and rhabdomyolysis or who have been diagnosed with myopathy or rhabdomyolysis when treated with an HMGCoA reductase inhibitor that is metabolized by P450 3A4, such as e.g. atorvastatin, simvastatin and lovastatin.

A further aspect of the invention is the aspects already described herein, wherein the dose of the Agent is 5 to 80 mg per day. Where reference is made in the specification to an Agens dose of 5 to 80 mg per day, other dosage ranges that constitute an independent aspect of the invention include (if appropriate) doses ranging from 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 doses may be e.g. 5, 10, 20, 40 and 80 mg per day. A particularly preferred initial dose of the Agent of the invention is 5 to 10 mg per day, especially 10 mg per day.

P450 3A4 substrates include: acetaminophen, aldrin, aflentanil, amiodorane, astemizole, benzphetamine, budenoside, carbamazepine, cyclophosphamide, cyclosporin, dapsone, digitoxin, diltiazem, diazepam, erythromycin, etoposide, lidopine, flutamide, flutamide, flutamide, flutamide lovatidine, losartan, lovastatin, midrazolam, nifedipine, omeprazole, quinidine, rapamycin, retenic acid, steroids, tacrolimus, teniposide, teophyline, toremifene, triazolam, troleandomycin, verapamil, warfarin, zatosetron and zonis.

P450 3A4 inhibitors include: clotrimazole, ethinylestradiol, gestodene, itraconazole, ketoconazole, miconazole, diltiazem, naringenin, erythromycin, cyclosporine and triacetyloleandomycin.

P450 3A4 inducers include: carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, sulfadimidine, sulfinipyrazone, and triacetyloleandomycin.

Examples of other P450 inducers, inhibitors or substrates include: Drug Metabolism Reviews (1997) Vol 29, Issue 1 + 2, p. 413-580, Rendic, S. and Di Carlo, F. J. "Human cytochrome P450 enzymes ,: A status report summarizing their reactions, substrates, inducers and inhibitors".

Agensa doses are administered according to the desired cholesterol lowering effect ranging from 5 to 80 mg per day in any number of unit dosage forms. Doses of a drug that is an P450 3A4 inducer, inhibitor or substrate are those recommended for each of these drugs that are commercially available. Advantageously, due to the absence of interaction at the P450 3A4 level, one of ordinary skill in the art can dispense the Agent with a drug that is an P450 3A4 inducer, inhibitor or substrate without the need for any adjustment. The dosage range and dosages described below are further independent aspects of the present invention.

Preferably, the agent is the calcium salt of bis [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3, 5-dihydroxyhept-6-ene] (see formula (I) in Figure 1).

DETAILED DESCRIPTION OF THE INVENTION

The experiment described below was used to determine the metabolic fate of the in vitro ^[14 C] -labeled agent in human hepatocytes and, in addition, to determine the specific P450 isoenzymes is involved in the metabolism of ^[14 C] -labeled agent. The latter experiment included the determination of the effect of selective chemical inhibitors of P450 (see Table 1) on the metabolism of [ ¹⁴ C] -labeled Agens.

Compound: [ ¹⁴ C] -labeled Agent

Chemical name: calcium salt of bis [(E ') -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) - 3,5-dihydroxyhept-6-ene]

Isomer: 3R, 5S, 6E stereoisomer

Molecular Weight: 1001,16 (Ca salt)

Formulation ingredients: The labeled Agent is dissolved in water to provide a solution suitable for administration to incubated samples

Tissue sources: human liver, suitable for the preparation of microsomes and hepatocytes, obtained from The International Institute for the Advancement of Medicine (Exton, USA). In addition, human hepatocytes may be obtained from Biowhittaker Ltd. or the United Kingdom Human Tissue Bank (Leicester, England).

Experimental procedures

1) Metabolism of [ ¹⁴ C] -labeled Agents in Human Hepatocytes [ ¹⁴ C] -labeled Agents (1 μΜ or more if necessary due to sensitivity of the analytical equipment) were incubated with hepatocytes in culture obtained from two organ donors. Cultures were stopped with ethanol after 0, 6, 24 and 48 hours incubation and stored at -20 ° C until analysis. Metabolic competence was verified at the time of incubation by examining their ability to metabolize [ ¹⁴ C] -ethoxycoumarin (25 μΜ); aliquots were taken from methanol at the same time as the test compound.

After incubation of [ ¹⁴ C] -ZD4522 with hepatocytes, a metabolic profile was generated using HPLC (high performance liquid chromatography). The ability of cells to metabolize [ ¹⁴ C] -ethoxycoumarin was confirmed by HPLC. Data evaluation

The data obtained were evaluated for the following:

(a) assessing whether human hepatocytes metabolize [ ¹⁴ C] -labeled Agents

(b) the quantity of each of the metabolites formed.

[ ¹⁴ C] -labeled Agents (at appropriate concentrations) were incubated with human liver microsomes in the presence or absence of P450 inhibitors (see Table 1). Similar incubations of [ ¹⁴ C] -labeled Agents with individual heterologously expressed P450 isoenzymes were also performed. Incubations were stopped by addition of a suitable organic solvent. Metabolic profiles of the incubated samples were prepared by HPLC.

Table 1

Selective chemical inhibitors of P450 isoenzymes

Isoenzyme P450 Selective inhibitor 1A2 furafylline 2C9 sulphaphenazole 209 omeprazole 2D6 quinidine 3A4 ketoconazole

Data evaluation

Data from this study were evaluated for the following aspects:

(a) the rate and extent of metabolism of [ ¹⁴ C] -labelled Agens,

b) comparing the ability of selective inhibitors reduce P450 metabolism ^{of [14} C] -labelled agent to determine (i) isozyme (s) involved in the metabolism of ^[l4 C] -labelled agents evaluate the ability of the individual expressed P450 isoforms to metabolise ^[I4 C] -labelled agent to determine (i) isozyme (s) involved in the metabolism of ^[14 C] -labelled agents

(c) in vitro results were used to predict the variability of Agensa pharmacokinetics in the population and the likely effects on Agensa pharmacokinetics when combined with known P450 enzyme inhibitors / inducers.

The Agent was found not to be significantly metabolised by whole hepatocytes, and was inhibited by sulphaphenazole and omeprazole.

Example 1

Use for the treatment of hyperlipidemia and associated disorders in transplant patients treated with immunosuppressive agents

Cytochrome P450 3A4 is a metabolised two basic drugs used to suppress the immune system in humans, namely cyclosporine and tacrolimus (formerly called FK506).

In particular, cyclosporin is additionally known as an inhibitor of P450 3A4 and can therefore be expected to reduce the metabolism of any drug also metabolized by P450 3A4. Thus, when prescribed immunosuppressive therapy, e.g. medicines such as cyclosporine and tacrolimus (especially cyclosporine), the attending physician must be cautious with respect to any other therapy combined in the same patient. Immunosuppressive therapy is most commonly used before, during and after transplantation in humans. In particular, in heart transplantation, the attending physician may want statin therapy for the patient to reduce the incidence of other coronary artery disease, heart attack, stroke, peripheral vascular occlusion or peripheral vascular disease, particularly in patients with elevated cholesterol levels or in patients with normal lipidemia, but with other risk factors for heart disease. Especially in this special group (transplant patients) there are patients at high risk of accelerated development of atherosclerosis in the transplanted organ, in a regressive manner and in a very short time, partly due to surgical damage of blood vessels during transplantation, earlier untreated diseases and immunosuppressive therapy. Hyperlipidemia is widespread after transplantation, even in patients who have not suffered from hyperlipidemia prior to transplantation, with an incidence of 60-80% of transplant recipients.

It is known that some immunosuppressive drugs such as e.g. steroids, cyclosporine and tacrolimus, increase cholesterol levels in patients (Wierzbicki AS (1999) IJPC S3 (1) 45-59). In addition, cyclosporin and tacrolimus may also increase fibrinogen and lipoprotein (a) levels in patients, further accelerating the progression of atherosclerosis in transplant patients (Hohaye H, Clin. Transplant (1997) 11, 225-230, Hilbrands LB, J. Am. Soc. Nephrol (1995) S, 2073-2081). Such unusually accelerated atherosclerosis occurs in about 20% of patients in the first year after transplantation and in about 40 to 65% in the fifth year (Chang G. et al. American Heart Journal (1998), 136 (2), 329-334). The incidence of accelerated atherosclerosis has been reported to cause 1 to 18% of CHD in the first year and 20 to 50% of CHD in the third year after heart transplantation (Erdoes LS, J. Vas. Surg. (1995) 22, 434-440). Lovastatin, pravastatin and simvastatin have been shown to lower cholesterol levels in heart transplant patients. In a placebo control study, pravastatin increased transplant survival by one year and significantly reduced the incidence of organ haemodynamic rejection. Due to the lower incidence of serious interactions with immunosuppressive therapy, pravastatin is currently the first choice drug for statin therapy in post-transplant treatment regimens. However, as noted herein, pravastatin does not reduce lipid / cholesterol levels as much as e.g. atorvastatin.

We have discovered that the Agent was extremely effective in treating hypercholesterolemia in transplant patients and is not metabolized by the cytochrome P450 isoenzyme 3A4. Using Agensa in a clinical study, it has been found that Agents can be appropriately administered to patients who receive immunosuppressive therapy without experiencing the side effects associated with the concomitant administration of Agensa and immunosuppressants, and moreover, it achieves a much greater reduction in cholesterol levels than before, e.g. using drugs such as pravastatin.

Thus, a first aspect of the present invention relates to a safe, non-interacting cholesterol lowering therapy in patients undergoing immunosuppressive chemotherapy, which therapy comprises administering to the patient an Agensa.

Patients who receive immunosuppressive chemotherapy and may benefit from the combination of the invention are characterized as follows:

(1) suffer from primary (type IIa) hypercholesterolaemia (LDL-L> 135 and TG <200), (2) suffer from mixed (type IIb) hypercholesterolaemia LDL-C> 135 and TG> 200), (3) patients with developed CHD or other atherosclerotic disease, such as e.g. PVD, stroke or occlusive peripheral vascular disease; (4) patients at high risk of developing CHD or other atherosclerotic disease as described herein due to a combination of risk factors. The term "high risk" is defined in the "Recommendations of the Second Joint Task Force on European and Other Societies on Coronary Prevention", (Wood, D. et al. European Heart Journal, Atherosclerosis and Journal of Hypertension 1998) as an absolute risk of CHD> 20% over 10 years or over 20% for a projection of 60 years. Whether the patient is at high risk can be determined using the charts attached to the recommendation "Recommendations ...". So eg. A male patient in his forties who has a systolic blood pressure of 180 mm Hg or greater and a total plasma cholesterol concentration of 7 mmol / l or greater is classified as a high risk patient. Similarly, other instructions for reducing risk factors, such as e.g. published in:

a) JAMA, June 16, 1993-Vol 629, No.23, Pages 3015-3023 - - &quot; Summary of the NCEP Adult Treatment Panel II Report &quot; 1 on p. 3018-3019.

(b) Post Graduate Medical Journal 1993; 69 (81 1): 359-369 - “Management of hyperlipidaemia: guidelines of the British Hyperlipidaemic Association” - especially tab. V and tab. VI.

c) Heart 1998; 80 Supplement 2: S1-S29 - “Joint British Recommendations for Coronary Heart Disease Prevention in Clinical Practice” - especially Fig. 1 on p. S4-S5.

(d) The Lancet 1995; December 2, Vol.346, 1467-1471 - "Sheffield Risk and Treatment Table for Cholesterol Lowerinc for Primary Prevention of Coronary Heart Disease" - especially the table on p. 1468th

(5) Patients suffering from type I or II diabetes; (6) patients who are preparing for or have just undergone a heart transplant.

In patients with ongoing immunosuppressive chemotherapy, statin therapy may be administered to achieve:

(1) reduction of atheroma plaque thickness in coronary arteries by> 30% when measured by IVUS, (2) LDL-C reduction by at least 30, 40, 50%, (3) maintenance or increase of HDL-C by at least 5, 10, 15 (4) a change in any of the above-mentioned values for the better than that achieved by using pravastatin at a similar dose over the same time,

Another feature of the invention is that since the Agent is not metabolised to a significant extent by the P450 isoenzymes, administration of the Agent to patients undergoing immunosuppressive fibrate therapy is much safer than before. As previously mentioned, fibrate and statin administration has previously been associated with a higher incidence of rhabdomyolysis and myopathy. In addition, fibrate drugs interact with cyclosporin due to the fact that both drugs are metabolized by the same P450 isoenzyme. Thus, the use of a statin and fibrate drug in combination with immunosuppressive therapy has previously been contraindicated due to the high likelihood of serious interactions (Hunninghake 1992, Wanner C. Kidney Int. (1995) 52 (suppl.), 560-562; Katznelson S. Contributions Nephrol. (1997) 120: 97-104. However, if possible, the administration of fibrates with statins may be advantageous as fibrates reduce lipoproteins other than statins, and thus their combination could further reduce the likelihood of CHD and other diseases already mentioned herein associated with the development of atherosclerosis due to complementarity. Thus, the ability to combine an agent that is not metabolized by P450 3A4 with fibrate and immunosuppressive therapy offers additional possibilities for lowering cholesterol in patients to a greater extent and more safely than before when administering statin, fibrate and immunosuppressants. ¹

Fibrate drugs are believed to act through the peroxisome proliferator activator (α) and affect the gene activation of many genes involved in atheromas. Fibrate-treated patients exhibit improved distribution of LDL subfractions (decreased VLDL and increased HDL), decreased LDL and reduced triglyceride levels, and the potential benefits of increased insulin sensitivity. Examples of fibrate drugs include bezafibrate, ciprofibrate, fenofibrate and gemfibrozil.

The term "safe non-interacting statin therapy" in the present application means that the Agent is not metabolized by P450 3A4 and therefore does not affect the metabolism of immunosuppressants and vice versa.

Diseases and disorders for which immunosuppressive therapy is prescribed include autoimmune diseases such as rheumatoid diseases such as rheumatoid arthritis, osteoarthritis, lupus erthematosus, and other autoimmune diseases such as idiopathic anthemic thymbocytopenia acute glomerulonephritis.

The agent may be administered at the same time as the immunosuppressive chemotherapy, and if not at the same time, at a relatively short interval after the administration of the immunosuppressive agent, e.g. on the same day, or within 6, 3, 2, or 1 hour.

The agent is administered according to the desired cholesterol lowering effect at a dose of 5 to 80 mg per day in any number of unit dosage forms, preferably in a single dose per day. Preferred doses are 10, 20 and 40 mg once daily. More preferred dosages are 20 and 40 mg once daily.

Particular immunosuppressive drugs that can be combined with an Agent are immunosuppressive drugs that are metabolized by liver enzymes, e.g. P450 3A4, thus, it is unlikely that drug interaction with the Agent will occur. Examples include the aforementioned cyclosporine and tacrolimus, as well as corticosteroids, which are also metabolized in the liver. Examples of corticosteroids include prednisone (mainly used in organ transplants). When more than one immunosuppressive drug is used, it is preferable to use either cyclosporin or tacrolimus, preferably cyclosporin.

The following non-limiting example is a clinical study demonstrating the efficacy of said aspects of the present invention.

Experimental protocol

Name of the study:

A double-blind, parallel-group study to evaluate changes in atheroma load of coronary arteries after heart transplantation as measured by IVUS after 12 months of administration of Agensa or pra7 vastatin

Study objectives:

The primary objective of the study was to measure changes in the maximum mean intimal thickness of the anterior descending cardiac artery using intravascular ultrasonography (IVUS) (central subtraction) after 12 months of administration of either Agensa or pravastatin. A change from baseline> 30% in intimal thickness was considered clinically significant.

The secondary objective of the study was to measure the effects of atheroma load on coronary arteries and to compare the effects of Agens with the following evaluations:

- evidence of organ rejection, as assessed on the basis of the adverse event report,

- measurement of LDL-C, HDL-C, apo B, apo A-I, Lp (a), ex vivo platelet aggregation, fibrinogen, PAI-I and circulating vascular inflammatory markers concentrations,

- comparison of lipid values after 52 weeks of treatment,

- measurement of inflammatory mediators after 52 weeks (HLA VCAM / ICAM expression evaluated by biopsies),

- determination of safety and tolerability of the drug.

Type and number of patients:

men and women (18 years of age and older) after heart transplantation suffering from hypercholesterolaemia and with triglycerides <400 mg / dl at the time of randomization into the study

Experimental treatment:

Once a day a dose of Agensa (10 mg) or pravastatin (10 mg) for two weeks, then titrating the doses to 20 mg Agensa and 20 mg pravastatin. After four weeks, doses may be titrated to 40 mg Agensa or 40 mg pravastatin. In patients who have been increased the dose up to 40 mg, it may be reduced again to 20 mg at the discretion of the attending physician.

Duration of treatment:

Eligible patients were randomized to one of two groups treated with either Agent or pravastatin at 52 weeks.

Primary measurement:

Mean deviation from baseline of maximum intimal thickness, evaluated by IVUS (central deduction).

Secondary measurement:

Percent changes in LDL-C at 6 and 12 months.

Percentage changes from baseline total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), LDL-C / HDL-C, TC / HDL-C, nonHDL -C / HDL-C and triglycerides (TG). Percent changes from baseline in apo B, apo B / apo A-1, apo A-1, Lp (a) and particle subfractions at 6 and 12 months.

Percentage of patients at each of the possible titrated doses at 12 months.

Endocardial rejection is considered an adverse event.

Percentage changes from basal inflammatory mediators (HLA antigen level and ICAM / VCAM expression).

Safety assessment based on the occurrence of adverse events, physical examination and laboratory examination data.

Study plan

This is a randomized, double-blind, parallel-group clinical trial conducted in several centers. At 1 to 4 weeks post-transplantation, patients were randomized to receive either Agents or pravastatin for 52 weeks. Treatment was started with doses of 10 mg of both Agent and Pravastatin at Visit 2, then the dose at Visit 3 was titrated to 20 mg during the forced titration period. At Visit 4 and subsequent visits, the attending physician could choose to increase the dose up to 40 mg during the optional titration period. In patients whose dose was increased up to 40 mg, it could be reduced again to 20 mg at the discretion of the attending physician.

Clinical trial design

before necessary Optional titration transplant titration

visit 1 2 3 4 5 6 7 8 9 10 11 week (W) / month (M) WO W2 W4 M2 M3 M4 M5 M6 M9 M12 Agent (mg) 10 20 > 20 * pravastatin (Mg) 10 20 > 20 *

Randomization ** * Patients who tolerated 20 mg of Agensa or pravastatin at Visit 4 could be titrated up to 40 mg at the discretion of the investigator.

** Patients were to be randomized within 4 weeks of heart transplantation and should not receive any other lipid-lowering treatment after surgery.

Criteria for inclusion in the study (1) underwent heart transplant four weeks prior to randomization, (2) fasting TG concentration <4.52 mmol / L (400 mg / dl).

Criteria to exclude a patient from the study

Each of the following criteria is considered to be a study exclusion criterion:

(1) use of other cholesterol-lowering drugs or dietary supplements, or lipid-lowering food additives after transplantation prior to study entry, (2) a history of severe or hypersensitivity reactions to other HMG-CoA reductase inhibitors, (3) pregnant women, nursing women and women with the possibility of conceiving not using chemical or mechanical contraception or having a positive pregnancy test in serum (serum β-human choriogonadotropin [β-HCG] analysis), (4) patients with a history of diabetic ketoacidosis during the last 5 years are excluded, (5) ) uncontrolled hypothyroidism defined as a level of thyrotropic hormone (TSH)> 1.5 times ULN at Visit 2 or patients who have started thyroid replacement therapy over the last three months, (6) use of concomitant medications as detailed below - excluding immunosuppressants and diazepan, (7) concomitant alcohol abuse u and / or drugs, (8) active liver disease or hepatic dysfunction, defined by an increase> 1.5 times ULN at Visit 2 in any of the following liver function tests: ALT, AST or bilirubin, (9) serum CK> 3 times ULN at visit 2, (10) serum creatinine> 220 pmol / l (2.5 mg / dl), (11) cancer patients or a history of cancer who, in the opinion of the researcher, have more than a minimal chance of recurrence, ( (12) participation in another research drug clinical study less than 4 weeks prior to randomization to a clinical study; (13) patients randomized to double-blind treatment who subsequently discontinued treatment may not re-enter this clinical study; (14) serious or unstable health study or a psychological condition that, in the opinion of the researcher, would compromise the patient's safety or successful participation in the clinical study, (15) patients receiving cyclic hormone oral replacement therapy (HRT), cyclic oral contraceptive (OCT), progesterone depot injections, or patients whose non-cyclic HRT or OCT have started within the last 3 months.

Illegal medication

Group of medicines Generic name Antibiotics / antifungals erythromycin, erythromycin base, ethyl succinate, acetyl sulfisoxazole rifampicin fluconazole ketoconazole itraconazole

Antiepileptics / antidepressants phenytoin phenobarbital fluoxetine carbamazepine Acne treatment isotretinoin Anti-ulcer drugs cimetidine cisapride Systemic steroids triamcinolone acetonide triamcinolone diacetate betamethasone sodium phosphate betamethasone acetate hydrocortisone hydrocortisone acetate hydrocortisone sodium hydrocortisone sodium succinate cortisone acetate dexamethasone acetate dexamethasone prednisone methylprednisolone methylprednisolone sodium prednisone methylprednisolone prednisone methylprednisolone acetate antihistamines astemizole terfenadine Lipid regulation niacin / nicotinic acid probucol psyllium preparations clofibrate cholestyramine colestipol hydrochloride gemfibrozil atorvastatin lovastatin pravastatin (except study medication) simvastatin fluvastatin cerevastatín fish oil (at any dose) dietary lipid-lowering supplements lipid-lowering food additives Hormonal treatment a combination of estrogen and progesterone, which are biphasic or triphasic

Friedewald equation

The LDL-C level is calculated using the Friedewald equation as follows: For SI units (mmol / l):

LDL-C = total cholesterol - [HDL-C + triglycerides / 2,2)

For units other than SI (mg / dl):

LDL-C = total cholesterol - [HDL-C + triglycerides / 5)

Summary of the objectives of the NCEP (National Cholesterol Education Program o) to control lipids ³

NCEP risk category Target LDL-C (NCEP) There is no CHD / PVD and 1 or no risk factor <160 mg / dl There is no CHD / PVD and 2 or more risk factors <130 mg / dl Clinically apparent CHD / PVD <= 100 mg / dl

^and Second Report of 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.

Example 2

Use of a combination of Agensa and a fibrate drug or niacin for the treatment of hyperlipidemia and associated conditions

Myopathy and rhabdomyolysis have been associated with the administration of a statin in combination with gemfibrozil, niacin, cyclosporin or erythromycin (HMG-CoA reductase inhibitors, Hunninhake, Current Opinion in Lipidology, 1992, 3, 22-28), which are substrates for P450 3A4. In addition, adverse effects associated with the administration of a fibrate drug have also been reported to be aggravated by concomitant statin therapy, such as the incidence of influenza myositis-like syndrome, which occasionally occurs in patients receiving gemfibrozil, increasing by 5% of patients when given a statin.

The combination of a statin with a fibrate drug is contraindicated on the label and package leaflet of all commercially available statins both in the US and Europe. Despite the possibility of serious drug interactions, doctors prescribe combination therapy with a statin and a fibrate drug in patients with more severe hypercholesterolaemia, such as those with familial mixed hyperlipidaemia, where the risk of serious drug interaction is outweighed by the benefit of the combination therapy. When prescribing combination therapy with a fibrate drug and a statin, it is recommended that patients be regularly assessed for CK, typically every 6 weeks, unless a stable regimen is established. When muscle symptoms occur along with increased CK activity, treatment is stopped. But, as quoted from the United States Lipitor ™ label, "there is no guarantee that this monitoring of [CK levels] will prevent severe myopathy".

We have found that the Agent is extremely effective in treating mixed hyperlipidemia and hypertriglyceridemia in patients when combined with a fibrate drug and that the Agent is not metabolised by the cytochrome P450 isoenzyme 3A4. Therefore, when using Agensa in a clinical study, the inventors have found that Agens can be advantageously administered to patients who are also taking a fibrate drug, without any significant side effects associated with co-administration of Agensa and a fibrate drug. In addition, using Agensa and a fibrate drug, a much higher lipid lowering rate than previously achieved can be achieved. The combination is best used in mixed hyperlipidemia where all lipids, LDL, VLDL and TG are increased.

Thus, a first aspect of the invention relates to a safe, non-interacting combination lipid lowering therapy in a mammal, including a human, preferably a patient suffering from mixed hyperlipidemia and hypertriglyceridemia, comprising administering to the patient an agent and a fibrate drug or niacin.

The term "combination" according to the invention means that either (1) The agent and the fibrate drug in combination are administered together in one pharmaceutical formulation, or (2) The agent and drug are administered separately. When administered separately, the components of the combination are administered to the patient simultaneously or sequentially.

As used herein, the term "fibrate drug" refers to a class of drugs that are based on the structure / activity of fibric acid, and such drugs include the following commercially available versions of the drug: bezafibrate, clofibrate, ciprofibrate, fenofibate and gemfibrozil, preferably fenofibrate.

Patients who are preferably administered the combination of the invention include those already suffering from myopathy or rhabdomyolysis when treated with a statin and / or fibrate drug that is metabolized by P450 3A4.

Specific patients who may benefit from the method of the invention are those who:

(1) suffer from mixed (type IIb) hypercholesterolaemia (typically LDL-C> 135 mg / dl), (2) suffer from familial hypercholesterolaemia (types IV and V), (3) patients suffering from secondary hypercholesterolaemia in the following disease states:

(a) diabetes (type I or II),

b) nephrotic syndrome,

c) uremia,

d) hyperthyroidism,

(e) obstructive liver disease; (4) patients with established CHD or other form of atherosclerosis such as PVD, stroke or peripheral arterial occlusive disease; (5) patients at high risk of developing CHD or other form of atherosclerosis such as has already been described because they have a combination of risk factors. The term "high risk" is defined in "Recom11 mendations of the Second Joint Task Force of the European and Other Societies on Coronary Prevention", (Wood, D. et al. European Heart Journal, Atherosclerosis and Journal of Hypertension 1998) as an absolute risk of CHD. > 20% over 10 years or over 20% for a projection of 60 years. Whether or not the patient is at high risk can be determined by the records accompanying the recommendations herein, and these records are summarized here by reference. For example, a male patient who has been smoking for 40 years and has a systolic blood pressure of 180 mm Hg or greater and a plasma total cholesterol concentration of 7 mmol / l or greater is classified as high risk. Similarly, other guidelines for reducing risk factors, such as those described in:

a) JAMA, June 16, 1993, vol. 629, no. 23, pages 3015-3023, "Summary of the NCEP Adult Treatment Panel II Report," specifically Figure 1, p. 3018 - 3019

(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.

c) Heart, 1998, 80, Supplement 2: S1-S29 "Joint British Recommendations for Coronary Heart Disease Prevention in Clinical Practice", specifically Figure 1 on S4-S5.

d) The Lancet, 1995, Dec. 2, die 346, 1467-1471, "Sheffield Risk and Treatment Table for Lower Cholesterol for Primary Prevention of Coronary Heart Disease", specifically the table on page 1468.

Statin therapy may be administered to achieve in a patient receiving a fibrate drug or niacin:

(1) LDL-C reduction of at least 30, 40, 50, 60, 70 or 80%, (2) maintenance or increase of HDL-C of at least 5, 10 or 15%, (3) reduction of triglycerides of at least 10, 20 , 30 or 40%.

The combination of fibrate or niacin and Agensa may be administered as separate unit forms, which may be taken simultaneously or sequentially, or in a combined unit form. The combination of fibrate and Agensa also has an additive or synergistic effect on lowering LDL-C, maintaining or increasing HDL-C, or lowering triglycerides in the patient's blood.

In addition, the combination of niacin and Agensa may be administered as separate unit forms, which may be taken simultaneously or sequentially, or in a combined unit form. The combination of fibrate and Agensa also has an additive or synergistic effect on lowering LDL-C, maintaining or increasing HDL-C, or lowering triglycerides in the patient's blood.

The doses of Agensa to be administered are prescribed by the attending physician, who generally takes into account the severity of the disease, the age, weight and sex of the patient. However, typical doses are from 5 to 80 mg per day orally, preferably once per day in the form of an oral tablet.

The doses of fibrate drug or niacin to be administered in combination according to the invention are also prescribed at the discretion of the attending physician, taking into account all of the factors listed herein, as well as which drug to use.

For clofibrate (such as Atromid-S®), a typical dose of 20-30 mg / kg body weight of the dermis is divided in two or three oral doses after meals.

For bezofibrate (such as Bezalip®) a typical dose of 400 mg once daily is taken orally after a meal in the evening or in the morning.

For fenofibrate (such as Lipantil®) a typical dose is 200 mg once a day or 62 mg three times a day with food.

For gemfibrozil (such as Lopid®) a typical dose is 600 mg twice daily orally.

For cipofibrate (such as Modalim®), a typical dose is 100 mg once a day orally.

For niacin (NIASPAN®, extended release niacin formulation and preferred property), the 500 mg dose is one to four times daily, preferably two to four times daily.

A preferred fibrate drug is fenofibrate.

Preferably, the Agent is administered to a patient receiving niacin at a daily dose of 10 or 40 mg.

The invention is further illustrated by the following non-limiting example - a clinical study.

Clinical study

A randomized, uncontrolled, centralized, open label, triple-crossover study to evaluate the effects of the combined administration ('coadministration') of Agent and fenofibrate on the pharmacokinetics of each compound in healthy male volunteers.

Study objectives:

The primary objective of the study was to evaluate the effects of the combined administration of Agensa and fenofibrate on the pharmacokinetics of Agensa and fenofibrate, and the safety of volunteers was assured by clinical monitoring.

Type and number of volunteers:

healthy male volunteers.

Study plan:

Randomized, uncontrolled, centralized open labeled, triple-crossover study.

Study treatment:

The study consisted of three seven-day treatment periods (referred to as periods A, B, and C). The volunteers received the Agensa 10 mg capsule once a day for 7 days in random order. There is always at least 3 weeks between the two trial periods - a "washout" period.

Duration of treatment:

The study consists of three seven-day dosing periods (a total of 21 dosing days) with at least a 3-week 'washout' period between periods A, B and C.

Primary outputs:

The primary outputs are:

- AUC (0-24) and C _max for Agents, in the presence or absence of fenofibrate,

- AUC (0-8) and C _max for fenofibrate, in the presence or absence of Agens.

Secondary outputs:

Secondary outputs are:

- t _max , t 1/2 and C _min for Agent, in the presence or absence of fenofibrate, ^_ t _max , ie / 2 and C _min for fenofibrate, in the presence or absence of Agent,

- safety assessment: symptoms, blood pressure, pulse, ECG, clinical biochemistry and hematology, urine analysis

Clinical trial plan

Summary of procedures - general plan for periods A, B and C

Study days examination benefit The agent / fenofibrate or combination Pa TK 12-lead ECG Blood and urine tests kinetics agent Kinetics of fenofibrate Before the study + + + + ^a -1 + ^b 1 + + ^c + ^c 2 + + ^b + " + ^e 3 + + ^d + ^e 4 + + ^b 5 + 6 + + ^b + " + ^e 7 + + + + " + ^e 8 + ^b + ^d 9 + ^d 10 + ^b + " After the study + + + + ^a + ^d

^and Comprehensive examination of clinical biochemistry, hematology and paper urine examination.

^b Clinical biochemistry examination only: urea, creatinine, total protein, albumin, uric acid, total bilimbine (and unconjugated and conjugated bilirubin with increased total bilirabin), alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamaglutamyltransferin ), sodium, potassium, calcium, cholesterol, and triglycerides.

^c All pre-dose clinical study periods.

^d Only the clinical study period when the volunteers received Agents.

^e Only the clinical study period when volunteers received fenofibrate.

P = pulse, BP = blood pressure

Clinical Study Plan II.

Day 7 in periods A, B and C

Time P and BP (L) 12-lead ECG Blood and urine tests ^e Kinetics of Agens ^b Kinetics of fenofibrate ⁰ Food and fluids Before the dose + + + + B Batch (0 hrs) D 0.5 h + + 1 hour + + 2 hrs + + D 3 hrs + + + + 4 hours + + F, F 5 hours + + + + 6 hours + + 8 hours + + WITH 10 hrs + M 12 hours + + + F 14 hours WITH 18 hrs. + W 24 hours + + + ^a + 30 hrs + 48 hours + 54 hours + 72 hours + ^a +

^and Clinical biochemistry only: urea, creatinine, total protein, albumin, uric acid, total bilirubin (and unconjugated and conjugated bilirubin to increase total bilirubin), alkaline phosphatase, ALT, AST, gamaglutamyltransferase, CK, sodium, potassium, calcium, cholesterol and triglycerides.

^b Only the clinical trial period when the volunteers received Agents.

^c Only the clinical study period when volunteers received fenofibrate.

L = lying, P = pulse, BP = blood pressure, D = drink, S = snack, M = food, F = free access to approved liquids and food, W = free access to water only

Objectives of the study

Primary Goal:

The primary objective of this study was to evaluate the effects of the combined administration (coadministration) of Agensa and fenofibrate on the pharmacokinetics of both Agensa and fenofibrate,

Secondary goal:

This study had no secondary objective, the safety of volunteers was ensured by clinical monitoring.

Study plan:

Randomized, uncontrolled, centralized, open label, triple-crossover study.

Volunteers underwent three treatment regimes in random order:

- 10 mg Agensa capsules once daily for 7 days,

- 67 mg capsule of fenofibrate (Lipantil ^MT ) three times daily for 7 days,

- a combination of Agensa (10 mg) and fenofibrate (Lipantil ^MT , 67 mg 3 times daily) for 7 days.

There is always a "wash-out" period of at least 3 weeks (21 days) between the two trial periods.

Criteria for inclusion of the patient in the study

To be included in the study, volunteers must meet all of the following criteria

- a man between the ages of 18 and 65,

- normal clinical examinations, including medical history, resting ECG and 24-hour continuous ambulatory ECG (if not performed within the past 12 months),

- negative tests for serum hepatitis B surface antigen and hepatitis B antibody and normal ferritin levels in the last 12 months,

- weight differing by not more than 20% from the required weight (see Metropolitan Tables of Weight and Height).

Criteria to exclude a patient from the study

A volunteer must be excluded from the study if it meets any of the following criteria:

- use of other medicines (including drug and drug abuse),

- use of any other new chemical during the 4 months prior to the clinical study (a new chemical is a substance that has not yet been approved by the competent marketing authority),

- participation in another clinical study during the 3 months prior to the start of the study, except for non-invasive drug-free studies,

- any acute illness within 2 weeks prior to the start of the study,

- any clinically significant variation in the results of clinical biochemistry, hematology and urine analysis, moreover, the following values must not exceed the upper limit of normal: total bilirubin, ALT, AST and CC,

- risk (after consideration by the attending physician) of transmission (by blood or other body fluids) of HIV infection, hepatitis B or C,

- a confirmed or suspected personal or family history of adverse drug reactions or hypersensitivity to drugs with a chemical structure similar to that of the Agent or related statins, or fenofibrate or related fibrate drugs,

- a history of gastrointestinal disorders, liver, gall bladder or kidney disorders that affect the absorption, distribution, metabolism or excretion of drugs,

- a history of Gilbert's syndrome,

- if participation in the study would mean donating more than 1,350 ml of blood to the volunteer 12 months prior to the end of the study,

- excessive alcohol intake, defined as a maximum weekly intake of more than 28 units (1 unit equals a quarter of a beer or a measuring cup of a spirit drink),

- treatment in the previous 3 months with a drug that has a well-defined hepatotoxic potential (eg halothane),

- a clinical assessment of the volunteer status by the researcher or attending physician, on the basis of which he should not participate in the study.

Restriction of volunteers

- not to take any medicines (or over-the-counter medicines) from 96 hours before day 1 of the study until 72 hours after the last dose of Agensa or the morning dose of fenofibrate of each dosing period unless your doctor agrees in advance,

- starve from midnight at night before each day of the test and, on arrival, eat a light breakfast on the first to seventh experimental day,

- 24 hours after the first dose on the 7th trial day of each period, do not drive a car, bicycle, use tools or tools (drills, grinders, sharp tools),

- remain in the research facility 24 hours after the first dose on the 7th trial day of each period,

- not to smoke, not to eat grapefruits, grapefruit juice, liquorice and beverages and caffeine-containing foods (eg coffee, tea, cocoa, cola) from midnight before the first test day up to 72 hours after the last Agensa dose or morning dose of fenofibrate of each dosing period

- not to drink alcohol from 96 hours before the first test day up to 72 hours after the last dose of Agensa or the morning dose of fenofibrate of each dosing period,

- refrain from physical exertion from 96 hours before the first test day up to 72 hours after the last dose of Agensa or morning dose of fenofibrate of each dosing period,

- refrain from potentially hazardous work or activity from administering the first dose of Agensa or fenofibrate until medical examination after completion of the test,

- do not donate blood during the clinical trial and 3 months after the last dose.

Products, presentation and storage

Dosages and Administration

Agensa and fenofibrate capsules were administered orally with 200 ml of pure water to a volunteer sitting upright.

On days 1 to 7 of each treatment period, the volunteers are treated according to one of the schemes:

- 1x10 mg capsule of Agensa administered between 08.30 and 09.30 hours,

- 3 x 67 mg fenofibrate capsules, as follows:

1. a capsule administered between 08.30 and 09.30 hours;

2. a capsule administered between 16.30 and 17.30 hours,

3. a capsule administered between 22.30 and 23.30 hours,

- 1 x 10 mg Agensa capsule and 3 x 67 mg fenofibrate capsule, as follows:

Agensa capsule and 1 fenofibrate capsule administered concurrently between 08.30 and 09.30 hours

2. a capsule of fenofibrate administered with food between 16.30 and 17.30 hours;

3. a capsule of fenofibrate administered with food between 22.30 and 23.30 hours.

On Day 1 and 6 of each period, the volunteers visited the study site each day, and immediately after receiving a dose of Agens, fenofibrate or Agent / fenofibrate, they were allowed to leave the study site except on day 7, where they remained for 24 hours.

In the periods when volunteers were selected for fenofibrate, they received two additional doses of fenofibrate, which they took at home. Volunteers were given a crucible with fenofibrate to take it according to the above scheme. They were also given a preset alarm to ensure they were taking the dose at the right time, and also a daily answering machine to record that they had taken the dose. When Agens and fenofibrate were handed over to volunteers, tear marks were affixed to the relevant case report forms (CRFs). The researcher had to make sure that each volunteer was properly treated.

Clinical and laboratory examinations

Primary outputs

The following parameters were measured as primary outputs:

- AUC (0-24) and C _max for Agents, in the presence or absence of fenofibrate,

- AUC (0-8) and C ^ for fenofibrate, in the presence or absence of Agens.

Secondary outputs

The following parameters were measured as secondary outputs: tmax, t 1/2 / Cmm for the Agent, in the presence or absence of fenofibrate, ^_ t _max , t | _{/ 2} and Cminpre fenofibrate, in the presence or absence of Agens,

- safety assessment: symptoms, blood pressure, pulse, ECG, clinical biochemistry and hematology, urine analysis

Example 3

Pharmaceutical preparation

This example illustrates, but is not limited to, dosage forms suitable for use in the invention.

capsule mg agent 5.0 lactose 42.5 maize starch 20.0 microcrystalline cellulose 32.0 pregelatinized starch 3.3 Hydrotalcit 1.1 magnesium stearate 1.1

Capsules containing 1, 2, 5 or 10 mg of Agensa can be similarly prepared using appropriately greater or lesser amounts of lactose to maintain a total fill weight of 105 mg.

Abbreviations used

In short Term ALT alanine aminotransferase ALP alkaline phosphatase apo B apolipoprotein B 100 AST aspartate aminotransferase AUC the area under the concentration curve from zero to infinity AUC (0-t) the area under the plasma concentration vs. time curve from the last quantifiable concentration CABG coronary artery bypass graft C '-'max minimum concentration CK Creatinine

CVA cerebrovascular incident ECG electrocardiogram EAS European Society for Atherosclerosis EDTA ethylenediaminetetraacetic acid XGT gamaglutaryltransferáza HMG-CoA reductase 3-hydroxy-3-methylglutaryl coenzyme A HDL high density lipoprotein HPLC high performance liquid chromatography HRT hormone replacement therapy IU international units IVUS intravascular ultrasonography LDL low density lipoprotein LDL-C low density lipoprotein cholesterol MVA mevalonic acid NC cannot be calculated NCEP National Cholesterol Education Program NDSR National data system for research THC tetrahydrocannabinol TG triglyceride 11/2 terminal elimination half-life tmax time of maximum concentration TC total cholesterol TIA transient ischemic event TSH thyrotropic hormone ULN upper limit of the standard VLDL very low density lipoprotein

Claims (23)

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] pyrimidine acid. -5-yl] (3,5,5,5) -3,5-dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof, and a drug that is an inhibitor, inducer or substrate of P450 isoenzyme 3A4 as a combined product for simultaneous, separate or sequential use in therapy. The non-interacting drug combination of claim 1, wherein the second drug is an inhibitor or inducer of the P450 isoenzyme 3A4. A non-interacting drug combination according to any one of claims 1 or 2, wherein the second drug is used to lower cholesterol and is an inhibitor, inducer or substrate of the P450 isoenzyme 3A4. The non-interacting drug combination of claim 3, wherein the second drug is selected from bezafibrate, clofibrate, fenofibrate, gemftbrozil and niacin. The non-interacting drug combination of claim 4, wherein the second drug is fenofibrate. A non-interacting drug combination according to any one of claims 1 to 2, wherein the second drug is used to treat cardiovascular disease and is also an inhibitor, inducer or substrate of the P450 isoenzyme 3A4. The non-interacting drug combination of claim 6, wherein the second drug is selected from the group consisting of digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil and warfarin. A non-interacting drug combination according to any one of claims 1 to 2, wherein the second drug is used for immunosuppressive therapy and is an inhibitor, inducer or substrate of the P450 isoenzyme 3A4. The non-interacting drug combination of claim 8, wherein the second drug is selected from the group consisting of cyclosporin, tacrolimus, and a corticosteroid. A non-interacting drug combination according to any one of claims 1 to 9, wherein (E ') - 7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidine- 5-yl] (35, 55) -3,5-dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof is administered at a dose of 5, 10, 20, 40 or 80 mg per day. A pharmaceutical composition comprising (E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 4-fluorophenyl) 55) -3,5-dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof, a medicament that is an inhibitor, inducer or substrate of the P450 isoenzyme 3A4 and a pharmaceutically acceptable diluent, carrier or adjuvant. Pharmaceutical composition according to claim 11, characterized in that the second medicament is a substrate of P450 isoenzyme 3A4 and is selected from the group consisting of acetominophen, aldrin, aflentanil, amiodorane, astemizole, benzphetamine, budenoside, carbamazepine, cyclophosphamide, cyclosporine, dapsone, digitoxin. diltiazem, diazepam, erythromycin, etoposide, flutamide, hydroxyarginine, ifosfamide, imipramine, lansoprazole, lidocaine, lovatidine, losartan, lovastatin, midrazolam, nifedipine, omeprazole, quinidine, rapamycin, retenic acid, steroidide, steroidide, steroidide, steroidide, steroidide, steroidide, steroidide, steroid , troleandomycin, verapamil, warfarin, zatosetron and zonisamide. The pharmaceutical composition of claim 11, wherein the second medicament is an inhibitor of the P450 isoenzyme 3A4 and is selected from the group consisting of clotrimazole, ethinylestradiol, gestodene, itraconazole, ketoconazole, miconazole, diltiazem, naringenin, erythromycin, cyclosporine, and triacetyloleaol. The pharmaceutical composition of claim 11, wherein the second drug is an inducer of P450 isoenzyme 3A4 and is selected from the group consisting of carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, sulfadimidine, sulfinipyrazone, and triacetyloleandomycin. Medicament kit, characterized in that the first medicament comprises (E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - ( 3,55,5,5-dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof, and a second drug which is an inhibitor, inducer or substrate of cytochrome P450 isoenzyme 3A4. Medicament kit according to claim 15, characterized in that the second medicament is used to lower cholesterol and is an inducer, inhibitor or substrate of the P450 isoenzyme 3A4. The medicament kit of claim 16, wherein the second medicament is selected from the group consisting of bezafibrate, clofibrate, fenofibrate, gemfibrozil and niacin. Medicament kit according to claim 15, characterized in that the second medicament is used for the treatment of cardiovascular diseases and is also an inhibitor, inducer or substrate of the P450 isoenzyme 3A4. The medicament kit of claim 18, wherein the second medicament is selected from the group consisting of digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil and warfarin. Medicament kit according to claim 15, characterized in that the second medicament is a substrate of P450 isoenzyme 3A4 and is selected from the group consisting of acetominophen, aldrin, aflentanil, amiodorane, astemizole, benzphetamine, budenoside, carbamazepine, cyclophosphamide, cyclosporin, dapsone, digitoxin diltiazem, diazepam, erythromycin, etoposide, flutamide, hydroxyarginine, ifosfamide, imipramine, lansoprazole, lidocaine, lovatidine, losartan, lovastatin, midrazolam, nifedipine, omeprazole, quinidine, rapamycin, retenic acid, steroidide, steroidide, steroidide, steroidide, steroidide, steroidide, steroidide, steroid , troleandomycin, verapamil, warfarin, zatosetron and zonisamide. The medicament kit of claim 15, wherein the second medicament is an inhibitor of the P450 isoenzyme 3A4 and is selected from the group consisting of clotrimazole, ethinylestradiol, gestodene, itraconazole, ketoconazole, miconazole, diltiazem, naringenin, erythromycin, cyclosporine, and triacetyloleaol. The medicament kit of claim 15, wherein the second medicament is an inducer of P450 isoenzyme 3A4 and is selected from the group consisting of carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, sulfadimidine, sulfinipyrazone, and triacetyloleandomycin. Use of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3 R, 5 S) -3,5- dihydroxyhept-6-ene or a pharmaceutically acceptable salt thereof together with an inhibitor, inducer or substrate of P450 isoenzyme 3A4 for the manufacture of a medicament for use in treating a patient in need of administering an HMG-CoA reductase inhibitor and a second drug which is an inhibitor, inducer or substrate P450 isoenzyme. 3A4.