Atazanavir application in hiv infection therapy

FIELD: medicine.

SUBSTANCE: invention relates to method for reducing of LDL-cholesterol and/or triglyceride level increased due to therapy by HIV protease inhibitors in HIV-infected subjects. According to invention Atazanavir is administered in combination with other HIV protease inhibitor, metabolized cytochrom P450 monooxygenase in therapeutically effective amounts.

EFFECT: effective treatment due to Atazanavir ability to cytochrom P450 monooxygenase inhibition; increased concentration of HIV protease inhibitors without preparation dose.

3 cl

 

The technical field

This invention relates to a method of reducing the inevitable metabolic side effects in HIV-infected patients; the above side effects are likely to result from the application of one or more HIV protease inhibitors. In more detail the invention relates to the replacement of the HIV protease inhibitors, causing increased levels of low-density lipoprotein (LDL) in the blood and/or increased levels of triglycerides, an inhibitor of HIV protease, atazanavir, as well as to the possibility of combination of atazanavir with other similar drugs.

Background of invention

Combination antiretroviral therapy, including the use of protease inhibitors, has led to significant progress in the treatment of HIV infection. The HIV protease inhibitors can be used in conjunction with HIV any abscopal drugs of other classes, for example, nucleoside analog reverse transcriptase inhibitor or non-nucleoside reverse transcriptase inhibitors, or in conjunction with other HIV protease inhibitors and, often, together with nucleoside analog reverse transcriptase inhibitor and/or nucleoside reverse transcriptase inhibitors in the so-called "cocktails". It has been suggested that the combination of different protease is inhibitorof provides overcoming viral resistance (see, for example, U.S. patent 6, 100, 277). It is shown that the protease inhibitor ritonavir improves the pharmacokinetics of some other protease inhibitors, when used in combination with them (see for example, U.S. patent 6, 037,157).

Preparation of HIV protease inhibitors, already on the pharmacological market or passing stage clinical trials include saquinavir, indinavir, ritonavir, nelfinavir, APV, atazanavir, tipranavir and lopinavir. Atazanavir (also referred to as BMS-232632) is described in U.S. patent 5, 849, 911 and 6, 166, 004. U.S. patent 6, 087, 383 relates to crystalline salts of atazanavir bisulfate. Atazanavir is azapeptide inhibitor; currently he is undergoing revision and clinical analysis. Atazanavir has a high efficiency, favorable profile stability and bioavailability, which is provided by oral administration of one dose per day.

It is shown that therapy for HIV infection with HIV protease inhibitors is accompanied by certain metabolic disorders in a significant number of patients, including increased levels of low-density lipoprotein and triglycerides in the blood plasma. The increase of LDL-cholesterol and triglycerides in the blood plasma is a serious risk factor for the premature development of atherosclerosis and g is petriglieri and in addition, it may lead to the development of heart disease and pancreatitis. Individual protease inhibitors differ, depending on their influence on the lipid profile of blood serum, but, in General, according to the latest research, all inhibitors such cause data metabolic disorders. Ritonavir, apparently, has the greatest ability to modify lipid blood picture, while indinavir, nelfinavir, APV and saquinavir, obviously, have a less pronounced effect on the level of serum lipids. Elevated levels of LDL - cholesterol and triglycerides, which are associated with use of protease inhibitor, cause even greater anxiety especially when you want to use two or more inhibitors simultaneously.

The incidence of hyperlipidemia in HIV-infected patients ranges from 8% to 66% (see Pharmacotherapy, 1999, 19:281-289).

One possible solution to this problem is to use lipid-lowering drugs in those patients who have increased levels of lipids in the blood plasma on the background of inhibitors of HIV protease. However, the most widely used drugs of this series of inhibitors of 3-hydroxy-3-methyl-glutaryl-COA reductase inhibitors, or statins, are metabolized by microsomal oxidation system with which a portion of picogram P450. Thus, at least some statins, such as simvastatin and lovastatin, a cholesterol-lowering effect in HIV-infected patients taking protease inhibitors, can be achieved with standard doses of statins.

The invention

The invention relates to a method of lowering elevated LDL-cholesterol and triglycerides in the blood plasma of HIV-infected patients undergoing treatment with HIV protease inhibitors, which consists in applying to the above patients doses of atazanavir, causing sufficient inhibition of HIV, in combination with an HIV-inhibiting amount of at least one other inhibitor of HIV protease, which is metabolized by cytochrome P450.

A detailed description of the invention

The present invention is based on the surprising observation that atazanavir, in contrast to other inhibitors of HIV protease, has expressed no effect on LDL-cholesterol and triglycerides in the blood plasma when it is used in the standard inhibiting doses.

During the clinical study, which was attended by 98 HIV-inficirovannyh patients taking atazanavir in one year, there was marked increase of LDL-cholesterol and triglycerides in the blood. Thus, atazanavir most climbed the n for the treatment of HIV infection from patients with elevated LDL-cholesterol and/or triglycerides. It can be used alone, as monotherapy, or to be part of the so-called "cocktails", which may include other antiretroviral drugs such as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and other inhibitors of HIV protease. The invention also relates to a method for treating HIV infection in patients with elevated LDL-cholesterol and/or triglycerides in the blood plasma, which consists in applying to the above patients sufficient for inhibition of HIV number of atazanavir.

Atazanavir is particularly useful for the treatment of HIV-infected patients with elevated cholesterol and triglycerides, resulting from antiretroviral therapy, another inhibitor of HIV protease.

In phase II, randomized study of the safety and antiviral activity of each of the three daily doses of atazanavir (200 mg, 400 mg and 500 mg) were compared with similar properties proteasome inhibitor nelfinavir used three times daily at a dose of 750 mg of Twenty-one patients received nelfinavir in combination with stavudine and didanosine, while the ATV was used as monotherapy (within two weeks)and in combination with stavudine and didanosine 78 control patients (b is C prior HIV therapy) HIV-burden > 2000 copies per milliliter (C/ml). In patients taking atazanavir, there is a marked reduction in viral load compared with patients taking nelfinavir; in addition, patients of the first group had no marked changes in the levels of lipids, while the patients of the other group after four weeks of nelfinavir significantly increased the levels of total cholesterol, LDL-cholesterol and triglycerides.

In phase II, another two-stage randomized trial conducted already in three groups of patients, antiviral activity and metabolic effects of atazanavir in two different doses (400 mg and 600 mg) were compared with similar properties of ritonavir; each of the drugs used in conjunction with saquinavir for 48 weeks. Protease inhibitors were combined with two nucleoside reverse transcriptase inhibitors selected from the group including didanosine, stavudine, lamivudine and zidovudine. Selection of reverse transcriptase inhibitors (used in the following combinations: didanosine+stavudine, stavudine+lamivudine, didanosine+zidovudine or lamivudine+zidovudine) was based on the phenotypic sensitivity of the patient and on the choice of the drug, made by the attending physician during the examination. We used the following drug regimens:

atazanavir 400 mg QD (hedgehog the day, from lat. quaque die) + saquinavir 1200 mg QD + 2 nucleoside reverse transcriptase inhibitors;

atazanavir 600 mg QD+saquinavir 1200 mg QD + 2 nucleoside reverse transcriptase inhibitors;

ritonavir 400 mg QD + saquinavir 400 mg BID (twice a day, from lat. bie in die) + 2 nucleoside reverse transcriptase inhibitors;

Patients were subjected to antiretroviral therapy, which consisted of combined admission for at least 24 weeks protease inhibitor or non-nucleoside reverse transcriptase inhibitor. In stage 1 was randomly selected out of approximately 75 patients to assess the safety and antiviral activity proposed therapeutic schemes. After the initial safety assessment carried out in Stage 1, an additional 300 patients were randomly selected for Stage 2 of the study in order to assess the magnitude and duration of the reduction of HIV RNA levels compared with the baseline in plasma for 48 weeks. Two groups using atazanavir were compared with patients taking ritonavir, the average change of total cholesterol compared with baseline at 12 weeks of the study. The difference in the estimates for these pairwise comparisons amounted to 49.1 for a couple atazanavir dose of 600 mg - ritonavir, and 28.7 for a couple atazanavir dose of 400 mg - RIT is never. Total cholesterol was not increased in either group, taking atazanavir. The average deviation from the norm on a 12 week study was -20 mg/DL for the atazanavir dose of 600 mg and 5 mg/DL for atazanavir 400 mg, compared with deviations for ritonavir, which was 37 mg/DL. Approximately half of the patients were not deviations of selected indicators of cholesterol metabolism by 12 weeks of the study. LDL-cholesterol was not increased compared with baseline in any of the groups taking atazanavir.

Two groups of patients taking atazanavir, compared with patients taking ritonavir, the mean deviation of the level of triglycerides from baseline to 12 week study. The difference in the estimates for these pairwise comparisons was - 135.9 for a couple atazanavir dose of 600 mg - ritonavir, and - 155.2 pair atazanavir dose of 400 mg - ritonavir. The average deviation from the norm at 12 weeks was 5 mg/DL for the atazanavir dose of 600 mg and -14 mg/DL for atazanavir 400 mg, compared with deviations for ritonavir, which was 102 mg/DL. Both groups antiretroviral effect within 12 weeks was the same. This study demonstrates that patients with elevated levels of LDL-cholesterol and triglycerides in the blood plasma can be translated into therapy, including at sanawar, which effectively maintains viral suppression and reduces elevated levels of LDL-cholesterol and triglycerides. Thus, the present invention relates to an efficient and safe way to reduce LDL-cholesterol and triglycerides in the blood plasma, which is a good alternative to use of statins, since their use may lead to increased risk of additional side effects and reduce the effectiveness of other medicines.

Atazanavir can be used as a standalone product or in combination with one or more active substance that is effective against retroviruses, primarily HIV. Such active substances may be, for example, reverse transcriptase inhibitors such as zidovudine, didanosine, stavudine, or lamivudine, or a non-nucleoside reverse transcriptase inhibitors, for example, efavirenz or other HIV protease inhibitors.

Atazanavir usually obtained in the form of a weak organic base, but for pharmacological use it to make a pharmacologically acceptable additive salt of the acid, as described in U.S. patent 6, 166, 004. The most appropriate form for the pharmaceutical composition is bisulfate, disclosed in U.S. patent 6, 087, 383.

The claimed method is used with respect to HIV infection is clinically the patient, having elevated levels of LDL-cholesterol and/or triglycerides. In one embodiment, the method of this patient passed or passes antiretroviral therapy based on one or more inhibitor of HIV protease instead of atazanavir and has elevated levels of LDL-cholesterol and/or triglycerides in the blood plasma. Other HIV protease inhibitors can be used as a plain products or combined antiretroviral therapy, which also includes one or more antiretroviral drug other groups, such as nucleoside reverse transcriptase inhibitors or non-nucleoside reverse transcriptase inhibitors. These patients, despite the fact that they may be satisfactory viral suppression, belong to the group of risk on the probability of developing hyperlipidemia and premature development of cardiovascular disease.

Used herein, the term "elevated levels of LDL-cholesterol and triglycerides," revealed in a Practical clinical manual for the implementation of the National Cholesterol Education Program (NCEP), whose main goal is the prevention and control of high cholesterol in adults. In the last guide, published in 2001, levels of LDL-cholesterol in plasma>130 mg/DL and triglycerides > 150 mg/DL, sitouts the elevated or "high".

The method, as claimed in this invention is most suitable for those patients whose triglyceride levels in the blood plasma is >200 mg/DL, and for patients whose LDL-cholesterol is >160 mg/DL, and there are no risk factors or cardiovascular disease in history. The definition of "elevated LDL-cholesterol and triglycerides, of course, may have different meaning, because NCEP continues to analyze the risk factors for heart disease. It is assumed that the term "elevated levels of LDL-cholesterol and triglyceride levels will correspond to the current NCEP manual.

On the one hand, the claimed invention involves the exclusion of unwanted drugs (causing increased levels of LDL-cholesterol and/or triglycerides in the blood plasma) on the basis of HIV protease inhibitors from the above diagram and replace them effective for the inhibition of HIV protease number of atazanavir, which reduces the levels of LDL-cholesterol and/or triglycerides in the blood plasma.

The applied dose of atazanavir depends on such factors as weight, age and individual condition of the patient, and from its chosen method (method) therapy. In General, the daily dose ranges from 3 mg to about 1.6 grams per day for one person and can be taken dinras a day or be divided into two or three doses. Preferred for an adult dosage is 50-800 mg, more preferred 400-600 mg, and the most optimal single dose of 400 mg of the drug per day.

Pharmaceutical compositions containing atazanavir, which can be applied in the proposed method, described, for example, in U.S. patent 6, 166, 004 and 6, 087, 383. Dosage forms for oral administration include capsules, tablets and powder for slurry preparation.

It was found that atazanavir is an inhibitor of cytochrome P450 monooxygenase and, therefore, can improve pharmacokinetic other medicines, metabolisable this enzyme in particular, other HIV protease inhibitors such as saquinavir, indinavir, nelfinavir, APV, tipranavir and lopinavir. Thus, he acts like ritonavir, described in U.S. patent 6, 037, 157, namely increasing the concentration in the blood primenenyaemykh together with him inhibitor of HIV protease. One of the noticeable differences from ritonavir is that atazanavir may be used in combination therapy with other HIV protease inhibitors in average therapeutic dose, while for ritonavir requires the use of subtherapeutic doses. Due to the fact that atazanavir has a potentiating effect on effect other is the HIV protease inhibitors, metabolisable cytochrome P450-monooxygenases, administration of atazanavir with other HIV protease inhibitors can reduce the dosage of these inhibitors and to maintain an optimal level of viral suppression. For example, in the phase II study described above, the input dose of saquinavir may be reduced from the recommended for him 1200 mg three times a day, up to 1200 mg, administered once, when used in conjunction with atazanavir. Atazanavir may be used in combination with other HIV protease inhibitors to lower levels of LDL-cholesterol and/or triglycerides in patients with AIDS, undergoing therapy with protease inhibitors, this will be supported by optimal viral suppression.

A suitable dose of the inhibitor of HIV protease, which will be used in conjunction with atazanavir may be determined by the following method, which was used for the combination of atazanavir/saquinavir.

Atazanavir is a weak inhibitor of the cytochrome P450 FOR compared to nelfinavir and indinavir, with Ki2.4 microns. The last two compounds increase the duration of action of saquinavir [dosage 1200 mg three times a day (TID)] 392 and 364%, respectively, of a stable manner. Mnogomodovoi pharmacological study was conducted in order to determine whether n is to blogatize similar increase when using a combination of atazanavir and saquinavir. This study revealed a more than threefold increase in the duration of action of saquinavir, due to the combination of atazanavir with a maintenance dose of 1200 mg of saquinavir once daily, which is equivalent to the existing regimen of saquinavir - 1200 mg HS. Using a constant dosage of atazanavir has been studied a certain number of doses of saquinavir to establish its duration of action in these doses [AVC (area under the curve). Area Under the Curve)and minimum concentration (CMIN). Concentration Minimum) no comparison described in the literature. In a similar manner have been identified doses of other HIV protease inhibitors used in combination with atazanavir.

1. The way to reduce elevated LDL-cholesterol and/or triglycerides in the blood plasma of HIV-infected patients undergoing treatment with HIV protease inhibitors, which consists in applying to the above patients effective for inhibition of HIV-number of atazanavir in combination with inhibiting HIV-quantity of at least one other inhibitor of HIV protease, metabolisable cytochrome P450 by monooxygenases.

2. The method according to claim 1, wherein atazanavir is used in combination with an inhibitor of HIV protease selected from the group including saquinavir, indinavir, APV, nelfinavir, tipranavir or l is Panavir.

3. The method according to claim 2, wherein atazanavir is used in combination with saquinavir.



 

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