WO1997037649A1

WO1997037649A1 - Method of reducing nephrotoxicity

Info

Publication number: WO1997037649A1
Application number: PCT/US1997/005292
Authority: WO
Inventors: Helmut Kropp
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1996-04-04
Filing date: 1997-03-31
Publication date: 1997-10-16
Anticipated expiration: 1998-10-04
Also published as: AU2556597A

Abstract

A method of reducing nephrotoxicity is disclosed which utilizes the administration of a dehydropeptidase (DHP) inhibitor.

Description

TITLE OF THE INVENTION

METHOD OF REDUCING NEPHROTOXICITY

SUMMARY OF THE INVENTION

A method of reducing nephrotoxicity in a mammalian patient receiving a primary therapeutic agent is disclosed which comprises administering to said patient a dehydropeptidase inhibitor in an amount which is effective for reducing nephrotoxicity.

BACKGROUND OF THE INVENTION

The present invention relates to a method of reducing the nephrotoxicity of drugs in patients. Numerous drugs are known to cause nephrotoxic side effects when administered to patients. This serious side effect is a limiting factor in the use of these potent medications, so much so that the use of nephrotoxic medications is usually restricted by clinicians to those patients where withholding the drug is more serious than the risk of nephrotoxicity or harm which accompanies the reaction or adverse effect. The present invention thus serves to shift the balance toward facilitating the use of these potent medications, while reducing the incidence and severity of nephrotoxicity.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms and definitions apply unless otherwise indicated.

Nephrotoxicity is typically seen clinically as a decrease in renal function, causing a rise in serum creatinine (SC) and/or blood urea nitrogen (BUN) levels. Ordinarily a clinician upon noting a rise in SC or BUN will reduce the dosage or eliminate altogether any drugs from the regimen used which are known to cause nephrotoxicity. This may significantly worsen the primary condition of the patient, since limited secondary treatments for the underlying disease may be available. Reducing nephrotoxicity of primary therapeutic agents includes the treatment of patients before or after a nephrotoxic reaction is observed. Administration of the DHP inhibitor can be undertaken with or without the nephrotoxic agent, i.e., the separate or combined administration of the DHP inhibitor and primary therapeutic agent in the same or different pharmaceutical compositions, at the same or different times. The same or different modes of administration for the nephrotoxic drug and the DHP inhibitor are also contemplated. For example, the nephrotoxic drug may be one which is administered intravenously, and the DHP inhibitor may be administered by injection (IM or IV) or orally by mouth. All such combined methods of administration are included in the present invention.

As used herein, the primary therapeutic agent is a drug which causes a reduction in renal function in some patients, which can ordinarily be identified and measured by conventional means, e.g., rise in serum creatinine or blood urea nitrogen (BUN). Examples of primary therapeutic agents which fall within this category are numerous.

Primary therapeutic agents are drugs which are recognized to be common causes of nephrotoxicity, when used in therapeutic or higher doses, and include immunosuppressants, antiinfectives and chemotherapeutics used to treat cancer.

Among the immunosuppressants known to cause nephro¬ toxicity are cyclosporine, mycophenolate and related compounds. Cyclosporine is the preferred immunosuppressant which is used in combination with a DHP inhibitor. Dosages of the immunosuppressant are conventional or increased slightly as determined by the clinician in view of the patient's overall tolerance of these medications.

A primary indication for the present method of treatment involves immunosuppression in conjunction with organ or tissue trans¬ plantation. Immunosuppressants are regularly used in these procedures to reduce the likelihood of transplant rejection, and a primary limiting factor in the use of the immunosuppressants in the past has been the incidence and severity of nephrotoxicity of the immunosuppressant compounds. The present invention thus serves to facilitate the use of immunosuppressants in these patients. The antiinfectives known to cause nephrotoxicity can be broadly categorized as antibacterials, anti-fungal/pneumocystis compounds, anti-tubercular compounds and anti-virals. These categories are descriptive only, since many of the compounds have activity in more than one area.

Representative examples of antibacterials include the aminoglycoside antibiotics, for example, gentamicin, kanamycin, tobramycin, amikacin and netilmycin. Such antibiotics are used routinely in hospitalized patients with susceptible infections, and a primary limiting factor in using these antibiotics has been the incidence and severity of nephrotoxicity.

Representative examples of other antibiotics which can be used in the present invention include bacitracin; neomycin; metronidazole; trimethoprim; polymyxin; sulfa-type drugs, such as sulfisoxazole and sulfamethoxazole; methenamine; vancomycin; spectinomycin; chloramphenicol and the like. Nephrotoxicity is a factor which is considered by the clinician when these drugs are used, particularly when prolonged administration is necessary.

Representative examples of antifungal/pneumocystis drugs which are used in connection with the present invention include amphotericin B, pentamidine, pentamidine isoethionate and atavaquone.

Representative examples of anti -tubercular compounds which are used in connection with the present invention include rifampin, para aminosalicylic acid, isoniazid and capreomycin. Representative examples of antiviral compounds which are used in connection with the present invention include acyclovir, AZT, 3TC, vidarabine, cidofovir (Vistide®), lamivudine, saquinavir and valacyclovir.

When an anti-infective is used in the present invention, it is preferred that the antiinfective is a non-beta lactam. Non-beta lactams include antiinfectives which do not contain a beta lactam ring, such as the penicillins, carbapenems, cephalosporins and the like. Beta lactam antibiotics are not generally associated with nephrotoxic reactions. Representative examples of non-beta lactams include all of the antiinfectives recited above, and in particular, the following: gentamycin, tobramycin, amikacin, netilmycin, streptomycin, spectinomycin, vancomycin, polymixin B, lincomycin, metronidazole, neomycin, chloramphenicol and trimethoprim/sulfamethoxazole. Representative examples of chemotherapeutic drugs which can be considered in connection with the present invention for use in the treatment of cancer include: doxorubicin, dauonrubicin, carmustine, cisplatnin, methotrexate, plicamycin, streptazocin, 5-fluorouracil, Novantrone®, mechlorethamine, melphelan, mercaptopurine, L-asparaginase, bicalutamide, taxol and anastrozole. The nephrotoxicity of these drugs is reduced upon the administration of the dehydropeptidase (DHP) inhibitor. DHP inhibitors as a class are typified by cilastatin. This compound is included in the combination product imipenem/cilastatin (PRIMAXIN ®). Cilastatin and related DHP inhibitors are disclosed, for example in U. S. Patent No. 4,668,504 issued to Kahan, et al. on May 26, 1987, which is incorporated herein by reference.

The nephroprotective dose of the DHP inhibitor used to decrease the incidence and severity of nephrotoxicity experienced upon the administration of primary therapeutic agents can be varied within wide limits, depending upon the severity of the nephrotoxic reaction, judged by the clinician in view of the recommended dosage range, the overall condition of the patient and other factors. Representative (nephroprotective) dosages of the DHP inhibitor range from about 0.1 mg. per kg. to about 100 mg. per kg.

The DHP inhibitor can be given separate from the primary therapeutic agent which is implicated in the nephrotoxic reaction, or the drugs can be given in combination.

Typically the compounds are formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. This invention, therefore, also relates to a pharmaceutical composition which is comprised of a DHP inhibitor, alone or with a drug which is suspected of causing nephrotoxic reactions, and a pharmaceutically acceptable carrier. Formulating these compositions typically involves mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

For oral compositions, the pharmaceutical carrier employed may be, for example, a solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known in the art, such as glyceryl mono-stearate or glyceryl distearate, alone or with a wax.

Thus, if a solid carrier is used, the preparation can be in the form of a tablet, hard gelatin capsule, a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 0.025 mg to as high as about 1 g. When a liquid carrier is used, the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule or nonaqueous liquid suspension.

Injectable aqueous or oil solutions or suspensions are prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including other agents. The resulting solution may be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.

Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique.

Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01 %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

The method of treatment described herein is typically practiced by administering the DHP inhibitor orally or parenterally, preferably orally. The term 'parenteral' as used herein includes intravenous, intramuscular and intraperitoneal administration. The DHP inhibiting compound used in the present invention is useful in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.

Anions derived from inorganic or organic acids may be suitable for the preparation of salt forms of the DHP inhibitor. Representative examples are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2- hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate, napadisylate, napsylate, pamoate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, tosylate and undecanoate. Other anionic salts will be apparent to the ordinarily skilled chemist. Compositions for injection may be prepared in unit dosage form in ampoules or in multidose containers. The compositions may take such forms as suspensions, solutions or emulsions, oily or aqueous in nature, and may contain various formulating agents, such as diluents, buffers, preservatives and the like. Hence, the compound is present in combination with these pharmaceutically acceptable carriers.

Alternatively, the active ingredient may be in the form of a powder, which can be reconstituted with a suitable carrier such as sterile water, normal saline and the like at the time of administration. The powder can be in lyophillized or non-lyophillized form. Oral compositions are typically in the form of tablets, capsules, solutions or suspensions. Such compositions may likewise be packaged in unit dose or multidose containers. In these oral compositions, the pharmaceutically acceptable carriers may be comprised of diluents, tabletting and granulating aids, lubricants, disintegrants, buffers, sweeteners, preservatives and the like.

The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.01 % to about 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg to about 2000 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage is usually the compound in a sterile water or saline solution or in the form of a soluble powder intended for solution.

A preferred weight ratio of the primary compound : DHP inhibitor in the combination compositions is about 1 :1.

The most preferred DHP inhibitor used in the present invention is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclo- propanecarboxamide)-2-heptenoic acid, (cilastatin) or a useful salt thereof.

The compound used in the present invention provide suφrising and unexpected safety benefits in that the nephrotoxicity of primary therapeutic agents is reduced upon administration of the DHP inhibitor. This not only renders normal dosages of these nephrotoxic drugs safer to use in the majority of seriously ill patients, but facilitates the use of higher dosages of these important drugs in patients that are critically ill.

Claims

WHAT IS CLAIMED IS:

1. A method of reducing nephrotoxicity in a mammalian patient receiving a primary therapeutic agent which comprises administering to said patient a dehydropeptidase inhibitor in an amount which is effective for reducing nephrotoxicity.

2. A method of reducing nephrotoxicity in accordance with claim 1 wherein the dehydropeptidase inhibitor is cilastatin.

3. A method of reducing nephrotoxicity in accordance with claim 1 wherein the primary therapeutic agent is selected from immunosuppressants, antiinfectives and chemotherapeutics.

4. A method of reducing nephrotoxicity in accordance with claim 3 wherein the primary therapeutic agent is an immunosuppressant.

5. A method of reducing nephrotoxicity in accordance with claim 4 wherein the immunosuppressant is selected from the group consisting of: cyclosporine, mycophenolate and related compounds.

6. A method of reducing nephrotoxicity in accordance with claim 3 wherein the primary therapeutic agent is an anti-infective.

7. A method of reducing nephrotoxicity in accordance with claim 6 wherein the anti-infective is selected from antibacterials, anti-fungal/pneumocystis, anti -tubercular compounds and antivirals.

8. A method of reducing nephrotoxicity in accordance with claim 7 wherein the antiinfective is an antibacterial.

9. A method of reducing nephrotoxicity in accordance with claim 8 wherein the anti-infective is a non-beta lactam.

10. A method of reducing nephrotoxicity in accordance with claim 9 wherein the non-beta lactam is selected from the group consisting of: gentamicin; kanamycin; tobramycin; amikacin; netilmycin; bacitracin; neomycin; metronidazole; polymyxin; trimethoprim; sulfisoxazole; sulfamethoxazole; methenamine; vancomycin; spectinomycin; chloramphenicol; amphotericin B, pentamidine, pentamidine isoethionate; atavaquone; rifampin; paraaminosalicylic acid; isoniazid; capreomycin; acyclovir; AZT; 3TC; vidarabine; cidofovir (Vistide®); lamivudine; saquinavir and valacyclovir.

11. A method of reducing nephrotoxicity in accordance with claim 10 wherein the antibacterial is a non-beta lactam selected from the group consisting of: bacitracin; neomycin; metronidazole; polymyxin; trimethoprim; sulfisoxazole; sulfamethoxazole; methenamine; vancomycin; spectinomycin and chloramphenicol.

12. A method of reducing nephrotoxicity in accordance with claim 6 wherein the antiinfective is an anti-fungal/pneumocystis compound.

13. A method of reducing nephrotoxicity in accordance with claim 12 wherein the anti-fungal/pneumocystis compound is selected from the group consisting of: amphotericin B, pentamidine, pentamidine isoethionate and atavaquone.

14. A method of reducing nephrotoxicity in accordance with claim 6 wherein the antiinfective is an anti-tubercular compound.

15. A method of reducing nephrotoxicity in accordance with claim 13 wherein the anti-tubercular compound is selected from the group consisting of: rifampin, paraaminosalicylic acid, isoniazid and capreomycin.

16. A method of reducing nephrotoxicity in accordance with claim 6 wherein the antiinfective is an antiviral compound.

17. A method of reducing nephrotoxicity in accordance with claim 12 wherein the antiviral compound is selected from the group consisting of acyclovir, AZT, 3TC, vidarabine, cidofovir (Vistide®), lamivudine, saquinavir and valacyclovir.

18. A method in accordance with claim 3 wherein the primary therapeutic agent is a chemotherapeutic drug used to treat cancer.

19. A method in accordance with claim 14 wherein the chemotherapeutic drug is selected from the group consisting of: doxorubicin, dauonrubicin, carmustine, cisplatnin, methotrexate, plicamycin, streptazocin, 5-fluorouracil, Novantrone®, mechlorethamine, melphelan, mercaptopurine, L-asparaginase, bicalutamide, taxol and anastrozole.

20. A method of reducing nephrotoxicity in a mammalian patient receiving a primary therapeutic agent which consists essentially of administering to said patient a dehydropeptidase inhibitor in an amount which is effective for reducing nephrotoxicity.

21. A method of inducing immunosuppression in a mammalian patient without substantially causing nephrotoxicity which consists essentially of administering to said patient an immuno- suppressive effective amount of cyclosporine and a nephroprotective effective amount of a dehydropeptidase inhibitor.

22. A method in accordance with claim 21 wherein the dehydropeptidase inhibitor is cilastatin.

23. A pharmaceutical composition which comprises a primary therapeutic agent and a dehydropeptidase inhibitor in combination with a pharmaceutically acceptable carrier.