Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
2001-08-28
2004-11-30
Andres, Janet (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C514S002600, C514S588000, C424S085400, C530S351000
Reexamination Certificate
active
06824769
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to optimal compositions useful in treating HCV infections in humans. These compositions comprise alpha-interferon and an IMPDH inhibitor, wherein the IMPDH inhibitor is present in an amount such that a ratio of Cavg/Cmin is between 1 to 10, wherein:
Cavg is average plasma concentration produced by said IMPDH inhibitor in said human; and
Cmin is estimated trough concentration produced by said IMPDH inhibitor in said human.
The present invention also relates to methods of producing and using the optimal compositions to treat HCV infections in humans.
BACKGROUND OF THE INVENTION
Hepatitis C virus (“HCV”) infection is a common cause of viral hepatitis. It is estimated that 3% of the world's population is infected with HCV. (Clarke, B. E.,
Balliere's Clinical Gastroenterology,
14, No. 2, pp. 293-305 (2000). Until recently, alpha-interferon was the first therapy with proven benefit for treating HCV infection. Depletion of cellular guanine nucleotide reservoirs via inhibition of the NAD+-dependent enzyme, inosine monophosphate dehydrogenase (“IMPDH”), which is the rate-limiting enzyme in the de novo nucleotide biosynthesis, has been identified as an attractive target for anti-HCV therapy. See, VX-497,
Drugs of the Future,
25(8), pp. 809-814 (2000). Known inhibitors of IMPDH include Ribavirin, VX-497, mycophenolate mofetil (Cellcept™), tiazofurin and mizoribine. Recently, a combination therapy, using alpha-interferon and Ribavirin™, has shown greater efficacy in treating HCV infection than a monotherapy using either entity. However, the combination therapy is not problem free. Alpha interferon is known to cause side effects such as high fevers, headaches, nausea and depression. Ribavirin tends to increase these side effects, and also cause haemolytic anaemia. Hepatologists are reluctant to reduce the dosage of Ribavirin below 800 mg/day (see, Foster, G. R. and Thomas, H. C.,
Balliere's Clinical Gastroenterology,
14(2), pp. 255-264 (2000). The minimum effective dose of Ribavirin is not yet known.
Thus, there is a need for a therapy that takes advantage of the synergy and/or additivity observed between alpha-interferon and an IMPDH inhibitor in the combination therapy, but preferably without the drawbacks associated with the individual components of the combination therapy.
Thus, there is a need for an optimal composition for treating HCV infection in a human, comprising alpha-interferon and an IMPDH inhibitor.
There is also a need for a method for treating HCV infection in a human comprising the step of administering to said human an optimal composition comprising alpha-interferon and an IMPDH inhibitor.
There is also a need for a method for evaluating the suitability of a composition comprising an IMPDH inhibitor and alpha-interferon for optimally treating HCV infection in a human.
There is also a need for a method of producing an optimal composition for treating HCV infection in a human, wherein said optimal composition comprises alpha-interferon and an IMPDH inhibitor.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an optimal composition for treating HCV infection in a human, comprising alpha-interferon and an IMPDH inhibitor, wherein said IMPDH inhibitor is present in said composition in an amount such that a ratio of Cavg/Cmin is between 1 to 10;
wherein:
Cavg is average plasma concentration produced by said IMPDH inhibitor in said human; and
Cmin is estimated trough concentration produced by said IMPDH inhibitor in said human.
It is another object of the present invention to provide a method for treating HCV infection in a human comprising the step of administering to said human an optimal composition comprising alpha-interferon and an IMPDH inhibitor, wherein said optimal composition contains said IMPDH inhibitor in an amount such that a ratio of Cavg/Cmin is between 1to 10;
wherein Cavg and Cmin are as described above.
It is yet another object of the present invention to provide a method for evaluating the suitability of a composition comprising an IMPDH inhibitor and alpha-interferon for treating HCV infection in a human, said method comprising the steps of:
a. administering to said human said composition comprising said IMPDH inhibitor and said alpha-interferon;
b. determining average plasma concentration produced by said IMPDH inhibitor in said human (“Cavg”);
c. determining trough concentration produced by said IMPDH inhibitor in said human (“Cmin”);
d. calculating a ratio of Cavg/Cmin;
e. deeming said composition to be suitable for treating HCV infection if said ratio is between 1 to 10.
It is yet another object of the present invention to provide a method of producing an optimal composition for treating HCV infection in a human, wherein said optimal composition comprises alpha-interferon and an optimal amount of an IMPDH inhibitor, said method comprising the steps of:
a. administering to said human a first composition comprising a first amount of said IMPDH inhibitor and said alpha-interferon;
b. determining average plasma concentration produced by said first amount of said IMPDH inhibitor in said human (“Cavg”);
c. determining trough concentration produced by said first amount of said IMPDH inhibitor in said human “Cmin”);
d. calculating a ratio of said Cavg to said Cmin;
e. modifying said first amount of said IMPDH inhibitor in said first composition to produce said optimal composition wherein said ratio is between 1 to 10.
REFERENCES:
Wright et al., 1999, Hepatology vol. 30, No. 4, pt. 2, p. 408A.*
Markland et al., 2000, Antimicrobial Agents and Chemotherapy, vol. 44, pp. 859-866.*
Paul Glue, M.D., Ph.D., “The Clinical Pharmacology of Ribavirin”, Seminars in Liver Disease, vol. 19, 17-24, Supplment 1, 1999.
Khakoo et al., “Ribavirn and Interfero Alfa-2b in Chronic Hepatitis C: Assessment of Possible Pharmacokinetic and Pharmacodynamic Interactions”, Br. J. Clin Pharmacol, 46: 563-570, 1998.
Brunet et al., “Pharmacokinetics and Pharmacodynaics of Mycophenolic Acid in Stable Renal Transplant Recipients Treated with Low Doses of Mycophenolate Mofetil”, Transpl. Int. 13 [Suppl 1] S301-S305, 2000.
McHutchinson et al., “Combination Therapy With Interferon Plus Ribavirin for the Initial Treatment of Chronic Hepatitis C”, Seminars in Liver Disease, 19: [Suppl. 1] 57-65, 1999.
Chaturvedi Pravin
Ette Ene
Andres Janet
Badia Michael C.
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
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